One-pot synthesis of 1,4-disubstituted 1,2,3-triazoles from terminal acetylenes and in situ generated azides

Article abstract of DOI:10.1016/j.tetlet.2007.01.130

1,4-Disubstituted 1,2,3-triazoles were obtained by a high-yielding copper(I) catalyzed 1,3-dipolar cycloaddition reaction between in situ generated azides and terminal acetylenes. This one-pot, two-step procedure tolerates most functional groups and circu

Full text of DOI:10.1016/j.tetlet.2007.01.130

Tetrahedron Letters 48 (2007) 2097–2099
One-pot synthesis of 1,4-disubstituted 1,2,3-triazoles from
terminal acetylenes and in situ generated azides
*
´
Kristin Odlo, Edmund Andre Høydahl and Trond Vidar Hansen
School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, PO Box 1068, N-0316 Blindern, Oslo, Norway
Received 12 December 2006; accepted 24 January 2007
Available online 30 January 2007
Abstract—1,4-Disubstituted 1,2,3-triazoles were obtained by a high-yielding copper(I) catalyzed 1,3-dipolar cycloaddition reaction
between in situ generated azides and terminal acetylenes. This one-pot, two-step procedure tolerates most functional groups and
circumvents the problems associated with the isolation of potentially toxic and explosive organic azides.
Ó 2007 Elsevier Ltd. All rights reserved.
Multi-component reactions have received much atten-
tion lately, and have proven to be a very elegant and
rapid way to access highly functional molecules from
simple building blocks. Multi-component, one-pot
reactions generally afford good yields and are funda-
mentally different from two-component reactions in
several aspects.1 Over the past decade, several sequen-
tial multi-component reactions have been developed
into multi-component one-pot variants involving Passe-
rini-,2 Ugi-,3 and Mannich-type4 reactions. Moreover,
multi-component one-pot reactions result in fewer
operations by avoiding isolation, handling and chro-
matography. Hence, better yields are usually achieved.
azides was facile at ambient temperature in aqueous
solutions. Herein, we report that the product azide from
reacting sodium azide with ethyl bromoacetate under
neutral conditions can be further transformed to 1,4-
disubstituted 1,2,3-triazoles in a one-pot procedure.
Mixing ethyl bromoacetate with one equivalent of
sodium azide in aqueous t-BuOH solution (H2O/t-BuOH
1:1, 0.25 M) produced the desired organic azide in quan-
titative yield with short reaction times at ambient tem-
perature. In the presence of one equivalent of phenyl
acetylene and 5 mol % CuSO4Æ5H2O and 10 mol %
sodium ascorbate, the in situ generated azide was con-
verted to the desired 1,4-disubstituted 1,2,3-triazole 1
in 91% yield. By applying this methodology to other
terminal acetylenes several 1,4-disubstituted 1,2,3-triaz-
oles were obtained in 80–94% yields (Scheme 1).10
The recently discovered copper(I) catalyzed azide-acetyl-
ene ligation reaction5 produces exclusively 1,4-disubsti-
tuted 1,2,3-triazoles.6 This reaction has recently received
considerable attention due to its regiospecificity, quanti-
tative yields and the capacity to tolerate a wide variety
of other functional groups. Despite its growing impact
in the field of bioconjugation and materials science,7
the application of this reaction is still hampered by the
apprehension of handling organic azides since hydrazoic
acid is toxic and potentially explosive.8
The rich variety of terminal acetylenes employed dem-
onstrates the scope and functional group tolerance of
this protocol. LC–MS and 1H NMR analyses of the
crude reaction products confirmed the formation of a
single regioisomer,10 and the presence of N–H triazoles
in the reaction mixtures was never observed. In all cases,
the products were isolated either by simple filtration or
by aqueous workup. Trace amounts of copper in the
final product was removed by washing with 10% ammo-
nia buffer solution (pH = 8.5).
In connection with our efforts in developing one-pot cop-
per(I) catalyzed cycloaddition reactions,9 we discovered
that conversion of a-bromo ketones to the corresponding
In summary, a one-pot procedure for the direct conver-
sion of a-halo esters to 1,4-disubstituted 1,2,3-triazoles
has been developed. These reactions were efficiently per-
formed in neutral aqueous solutions (pH = 7–8) at
Keywords: One-pot reactions; 1,2,3-Triazoles; Cycloadditions.
*
Corresponding author. Tel.: +47 22857450; fax: +47 22855947;
e-mail: t.v.hansen@farmasi.uio.no
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.130

2098
K. Odlo et al. / Tetrahedron Letters 48 (2007) 2097–2099
Scheme 1.
Yamanaka, Y.; Miyazawa, T.; Kuwata, S. Synthesis
1998, 991–998; (c) Ross, G. F.; Herdtweck, E.; Ugi, I.
Tetrahedron 2002, 58, 6127–6133.
ambient temperature. Molar equivalents of the halide,
sodium azide, and alkyne were employed in this mild
1,3-dipolar cycloaddition reaction. The method circum-
vents the problems encountered with the isolation of or-
ganic azides, and complements other recently published
methods for the preparation of 1,2,3-triazoles.11 The
operational simplicity of this method makes it attractive
for preparative applications as well as for the synthesis
of screening libraries for drug discovery.
4. (a) Tramontini, M. Synthesis 1973, 703–775; (b) Arend,
M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed.
1998, 37, 1044–1070; (c) Wei, C.; Li, Z.; Li, C.-J. Org. Lett.
2003, 5, 4473–4475; (d) Wei, C.; Li, C.-J. J. Am. Chem.
Soc. 2003, 125, 9584–9585.
5. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596–
2599; (b) Tornøe, C. W.; Christensen, C.; Meldal, M. J.
Org. Chem. 2002, 67, 3057–3064; (c) Bock, V. D.;
Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem.
2006, 51–68.
Acknowledgement
6. Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry;
¨
Financial support to K.O. from the School of Phar-
macy, University of Oslo, is gratefully appreciated.
Padwa, A., Ed.; Wiley: New York, 1984; pp 1–176.
7. For recent examples see: (a) Malkoch, M.; Schleicher, K.;
Drockenmuller, E.; Hawker, C. J.; Russell, T. P.; Wu, P.;
Fokin, V. V. Macromolecules 2005, 38, 3663–3678; (b)
Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.;
References and notes
´
Scheel, A.; Voit, B.; Pyun, J.; Frechet, J. M. J.; Sharpless,
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2. (a) Bossio, R.; Marcaccini, S.; Pepino, R.; Torroba, T.
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Pepino, R.; Torroba, T. J. Chem. Soc., Perkin Trans. 1
1996, 229–230; (c) Bossio, R.; Marcos, C. F.; Marcaccini,
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A.; Cropp, T. A.; Mukherji, M.; Chin, J. W.; Anderson, J.
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J = 7.1 Hz, 3H), 2.09 (s, 3H), 4.03 (s, 2H), 4.17 (q,
J = 7.1 Hz, 2H), 5.32 (s, 2H), 7.65–7.80 (m, 4H), 7.92 (s,
1H), 8.03 (s, 1H), 10.31 (s, 1H); 13C NMR (75 MHz,
DMSO-d6): d = 13.88, 24.04, 38.60, 50.17, 61.35, 118.48,
124.61, 127.64, 133.82, 142.67, 167.02, 168.87; HRMS
calcd for C15H19N5O5S (M+): 381.1107, found: 381.1074;
10. General procedure as exemplified for ethyl 2-(4-((4-nitro-
phenylsulfonamido)methyl)-1H-1,2,3-triazol-1-yl)acetate
(4): ethyl bromoacetate (167 mg, 1 mmol), sodium azide
(65 mg, 1 mmol), and 4-nitro-N-(prop-2-ynyl)benzenesulf-
onamide (240 mg, 1 mmol) were mixed with t-BuOH:
ethyl
2-(4-((4-nitrophenoxy)methyl)-1H-1,2,3-triazol-1-
yl)acetate (6): white crystals (85%); mp 133–134 °C;
Rf = 0.58 (EtOAc/hexane 1:1); 1H NMR (500 MHz,
DMSO-d6): d = 1.22 (t, J = 7.1 Hz, 3H), 4.17 (q,
J = 7.1 Hz, 2H), 5.36 (s, 2H), 5.42 (s, 2H), 7.82 (dd,
J = 2.0 Hz, 9.1 Hz, 2H), 7.98 (dd, J = 2.0 Hz, 9.1 Hz, 2H),
8.29 (s, 1H); 13C NMR (125 MHz, DMSO-d6): d = 13.85,
50.33, 61.42, 71.70, 115.24, 125.74, 126.31, 140.95, 141.65,
163.06, 167.25; HRMS calcd for C13H14N4O5 (M+):
306.0964, found 306.0981; ethyl 2-(4-(4-nitrophenyl)-1H-
1,2,3-triazol-1-yl)acetate (7): yellow crystals (80%); mp
water solution (4 mL, 1:1) in
a 20 mL screw-top
scintillation vial. Sodium ascorbate (19 mg, 10 mol %)
and copper(II) sulfate solution (50 lL, 1 M, 5 mol %) were
added sequentially and the reaction mixture was stirred at
room temperature for 12 h. The reaction mixture was
diluted with cold water (15 mL) and 10% aqueous
ammonia (2 mL, pH = 8.5) was added. After stirring for
another 5 min, the precipitate was collected with a
1
144–145 °C; H NMR (300 MHz, DMSO-d6): d = 1.24 (t,
J = 7.0 Hz, 3H), 4.18 (q, J = 7.0 Hz, 2H), 5.52 (s, 2H),
8.13 (d, J = 9.0 Hz, 2H), 8.32 (d, J = 9.0 Hz, 2H), 8.85 (s,
1H); 13C NMR (75 MHz, DMSO-d6): d = 13.89, 50.63,
61.58, 123.70, 124.32, 125.90, 136.79, 144.38, 146.53,
166.98; HRMS calcd for C12H12N4O4 (M+): 276.0859,
found: 276.0841; ethyl 2-(4-(4-bromophenyl)-1H-1,2,3-
triazol-1-yl)acetate (8): white crystals (94%); mp 129–
131 °C; Rf = 0.57 (EtOAc/hexane 1:1); 1H NMR
(300 MHz, DMSO-d6) d = 1.23 (t, J = 7.1 Hz, 3H), 4.20
(q, J = 7.1 Hz, 2H), 5.46 (s, 2H), 7.66 (d, J = 8.6 Hz, 2H),
7.82 (d, J = 8.6 Hz, 2H), 8.61 (s, 1H); 13C NMR (75 MHz,
DMSO-d6): d = 13.90, 50.52, 61.53, 120.86, 123.03,
127.08, 129.69, 131.84, 145.25, 167.07; HRMS calcd for
C12H12BrN3O2(M+): 309.0113, found 309.0113; ethyl 2-(4-
(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-1-yl)acetate (9):
yellow crystals (88%); mp 95–96 °C; Rf = 0.18 (EtOAc/
Buchner filter and dried under vacuum. This afforded 4
¨
(299 mg, 81%) as white crystals; mp 154–155 °C; Rf = 0.41
(EtOAc/hexane 1:1); 1H NMR (500 MHz, DMSO-d6):
d = 1.28 (t, J = 7.1 Hz, 3H), 4.22 (q, J = 7.1 Hz, 2H), 4.38
(s, 2H), 5.31 (s, 2H), 7.92 (s, 1H), 8.06 (dd, J = 1.9, 8.8 Hz,
2H), 8.42 (dd, J = 1.9, 8.8 Hz, 2H), 8.67 (br s, 1H); 13C
NMR (125 MHz, DMSO-d6): d = 13.86, 37.79, 50.09,
61.13, 124.34, 127.93, 142.97, 146.10, 149.38, 166.98;
HRMS calcd for C13H15N5O6S (M+): 369.0743, found
369.0729. Spectral data of new compounds: ethyl 2-(4-
((4-methoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl)acetate
(2): white crystals (89%); mp 103–104 °C; Rf = 0.66
(EtOAc/hexane 1:1); 1H NMR (500 MHz, DMSO-d6):
d = 1.21 (t, J = 7.0 Hz, 3H), 3.70 (s, 3H), 4.19 (q,
J = 7.0 Hz, 2H), 5.10 (s, 2H), 5.40 (s, 2H), 6.62 (dd,
J = 1.9 Hz, 8.9 Hz, 2H), 6.96 (dd, J = 1.9 Hz, 8.9 Hz, 2H),
8.19 (s, 1H); 13C NMR (125 MHz, DMSO-d6): d = 13.94,
50.35, 55.32, 61.42, 75.12, 114.47, 115.65, 125.81, 142.98,
152.00, 153.56, 167.19; HRMS calcd for C14H17N3O4
(M+): 291.1219, found 291.1231; diethyl 2,20-(4,40-(4-
(methoxycarbonyl)-phenylenesulfonamido)bis(methylene)-
bis-(1H-1,2,3-triazole-4,1-diyl))diacetate (3): white crystals
1
hexane 1:1); H NMR (300 MHz, DMSO-d6): d = 1.24 (t,
J = 7.1, 3H), 3.69 (s, 3H), 3.85 (s, 6H), 4.21 (q, J = 7.1 Hz,
2H), 5.45 (s, 2H), 7.17 (s, 2H), 8.58 (s, 1H); 13C NMR
(75 MHz, DMSO-d6): d = 13.91, 50.47, 55.85, 60.00,
61.50, 102.44, 122.69, 126.04, 137.19, 146.39, 153.26,
167.16; HRMS calcd for C15H19N3O5 (M+): 321.1325,
found: 321.1325.
1
(89%); mp 141–143 °C; Rf = 0.35 (EtOAc/hexane 1:1); H
11. (a) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. Tetra-
hedron Lett. 2002, 43, 9707–9710; (b) Appukkuttan, P.;
Dehaen, W.; Fokin, V. V.; Eycken, E. V. D. Org. Lett.
2004, 6, 4223–4225; (c) Feldman, A. K.; Colasson, B.;
Fokin, V. V. Org. Lett. 2004, 6, 3897–3899; (d) Kamijo, S.;
Jin, T.; Huo, Z.; Yamamoto, Y. J. Org. Chem. 2004, 69,
2386–2393; (e) Chittaboina, S.; Xie, F.; Wang, Q. Tetra-
hedron Lett. 2005, 46, 2331–2336; (f) Loren, J. C.;
Sharpless, K. B. Synthesis 2005, 1514–1520; (g) Loren, J.
NMR (500 MHz, DMSO-d6): d = 1.22 (t, J = 7.0 Hz, 6H),
3.89 (s, 3H), 4.17 (q, J = 7.0 Hz, 4H), 4.52 (s, 4H), 5.33 (s,
4H), 7.81 (d, J = 8.3 Hz, 2H), 7.96 (s, 2H), 8.04 (d,
J = 8.3 Hz, 2H);13C NMR (125 MHz, DMSO-d6):
d = 13.85, 41.57, 50.19, 52.49, 61.36, 125.51, 127.24,
129.47, 132.97, 141.67, 143.02, 165.05, 167.00; HRMS
calcd for C22H27N7O8S (M+): 549.1642, found 549.1691;
ethyl 2-(4-((4-acetamidophenylsulfonamido)methyl)-1H-
1,2,3-triazol-1-yl)acetate (5): white crystals (88%); mp
´
C.; Krasinski, A.; Fokin, Valery V.; Sharpless, K. B.
Synlett 2005, 2847–2850.
1
176-178 °C; H NMR (300 MHz, DMSO-d6) d = 1.22 (t,