MeOPEG-bounded azide cycloadditions to alkynyl dipolarophiles

Article abstract of DOI:10.1016/S0040-4039(02)02844-7

The MeOPEG-supported azide 2 was reacted in the presence of a number of alkynyl dipolarophiles. The corresponding 1-MeOPEG-supported-1,2,3-triazoles were obtained in nearly quantitative yields. Acidic hydrolysis of the cycloadducts 5b and 6b caused the removal of the MeOPEG pendant giving 4-methoxycarbonyl-1,2,3-triazole 9 and 5-methoxycarbonyl-1,2,3-triazole 10, respectively.

Full text of DOI:10.1016/S0040-4039(02)02844-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1133–1135
MeOPEG-bounded azide cycloadditions to alkynyl
dipolarophiles
Luisa Garanti and Giorgio Molteni*
Universit a` degli Studi di Milano, Dipartimento di Chimica Organica e Industriale, via Golgi 19, 20133 Milano, Italy
Received 27 November 2002; revised 13 December 2002; accepted 16 December 2002
Abstract—The MeOPEG-supported azide 2 was reacted in the presence of a number of alkynyl dipolarophiles. The corresponding
1
-MeOPEG-supported-1,2,3-triazoles were obtained in nearly quantitative yields. Acidic hydrolysis of the cycloadducts 5b and 6b
caused the removal of the MeOPEG pendant giving 4-methoxycarbonyl-1,2,3-triazole 9 and 5-methoxycarbonyl-1,2,3-triazole 10,
respectively. © 2003 Elsevier Science Ltd. All rights reserved.
1
As it was disclosed from Huisgen’s works, the 1,3-
dipolar cycloaddition between organic azides and
alkynyl dipolarophiles represent the choice method for
the direct synthesis of variously substituted 1,2,3-tri-
The monomethylether of poly(ethylene glycol) with a
MW of 5000 (MeOPEG) was devised as the suitable
soluble support for our purposes. MeOPEG-supported
azide 2 was obtained by treating MeOPEG-mesylate 1
with sodium azide in anhydrous dimethylformamide
(Scheme 1).
1
0
2
azoles. The latter may display a wide range of biological
3
4
activity as anti-HIV and anti-microbial agents as well
5
as selective b adrenergic receptor agonist. Due to
3
these attractive activities, new methods for the regiose-
lective synthesis of these compounds should be of inter-
est. Within this context, it could be considered that the
polymer-supported synthesis of small heterocyclic6
molecules is the subject of intense research activity,
since it represents one of the most promising ways to
generate small molecular libraires in the field of combi-
First, in order to demonstrate the feasibility of the
soluble-polymer-supported azide cycloadditions, we
heated 2 in dry toluene and in the presence of an excess
of DMAD (10 mol. equiv.). 1-MeOPEG-supported-4,5-
bismethoxycarbonyl-1,2,3-triazole 3 was obtained with
98% yield as a white solid by simple precipitation from
11
the reaction crude with diethylether.
Structural
7
1
12
natorial chemistry.
assignements of 3 rely upon H NMR analysis and
are fully consistent with those of similar 4,5-
13
Recently, soluble polymers like poly(ethylene glicol)
bismethoxycarbonyl-1,2,3-triazoles.
8
(
PEG) and linear polystyrene (LPS) have gained popu-
larity among organic chemists due to a number of
advantageous features like the analytical simplicity, the
high reactivity and the low price of the starting materi-
als. Furthermore, the typical ease of the reaction work-
up parallels one of the most appreciated features of
solid-supported synthesis. The first example of 1,3-
dipolar intermediate linked to the PEG was described
Next, we reacted 2 with monosubstituted acetylenes 4
obtaining a mixture of the regioisomeric MeOPEG-sup-
14
ported cycloadducts 5 and 6 (Scheme 2). Products,
1
5
yields and product ratio are summarised in Table 1.
All cycloadditions were fully satisfactory in terms of
9
recently by Janda and co-workers and is concerned
with the generation of a supported nitrile oxide. Fol-
lowing this approach, we undertook the first study on
the 1,3-dipolar cycloadditions between the soluble-poly-
mer-supported azide 2 and a number of alkynyl
dipolarophiles.
*
0
Corresponding author. Tel.: +0039-02-50314141; fax: +0039-02-
0314139; e-mail: giorgio.molteni@unimi.it
5
Scheme 1.
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02844-7

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L. Garanti, G. Molteni / Tetrahedron Letters 44 (2003) 1133–1135
1
bonyl-1,2,3-triazole 10, respectively, with 83% overall
yield. In conclusion, the present study provides the first
insight into the cycloaddition between the MeOPEG-
supported azide 2 and a number of alkynyl dipolar-
ophiles. Further developments are in progress.
Acknowledgements
We thank the NMR specialist Dr. Lara De Benassuti,
1
University of Milan, for H NMR analyses of the
MeOPEG-supported materials.
Scheme 2.
Table 1. Cycloaddition between MeOPEG-supported azide
References
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+6
2
5:6
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Ph
COOMe
CH Cl
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96
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76:24
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–
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16
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7
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Figure 1.
11. The yields of MeOPEG-bounded materials were deter-
mined by weight of pure compounds. The purity of
1
MeOPEG-bounded compounds was determined by
H
NMR analyses with pre-saturation of the MeOPEG
methylene signals at 3.64 l.
1
1
2. H NMR data of 3 (CDCl ): l 3.28 (2H, t, J=7.0,
3
CH OCH6 –), 3.33 (3H, s, CH6 3OCH –), 3.80 (2H, t, J=
3
2
2
7
.0, –C H6 CH Nꢀ), 3.94 (6H, s, C H6 3COO–), 4.81 (2H,
2
2
t, J=7.0, –CH CH
6
2Nꢀ).
2
Scheme 3.
13. Zalkow, L. H.; Hill, R. H. Tetrahedron 1975, 31, 831.

L. Garanti, G. Molteni / Tetrahedron Letters 44 (2003) 1133–1135
1135
1
1
4. For a typical run: A solution of 2 (5.00 g, 1.0 mmol) and
(10.0 mmol) in dry toluene (40 mL) was refluxed for 20
6c: l 7.58 (1H, s, C -H
6
); 5d: l 7.84 (1H, s, C -H
6
); 6d: l
4
5
4
7.65 (1H, s, C -H
6
); 5e: l 7.78 (1H, s, C -H
6
); 6e: l 7.60
(1H, s, C -H6 ); 5f: l 7.62 (1H, s, C -H6 ); 6f: l 7.51 (1H, s,
4 5
4
5
h. Diethyl ether (50 mL) was added, the white precipitate
was collected by filtation off affording a mixture of the
MeOPEG-supported cycloadducts 5+6 (see Table 1).
C -H6 ).
4
16. Tsypin, G. I.; Timofeeva, T. N.; Melnikov, V. V.;
1
5. The following data are selected from the H NMR analy-
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ses of the mixtures 5+6 in CDCl solutions. 5a: l 7.97
13, 1395.
3
(
1H, s, C -H
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); 6a: l 7.65 (1H, s, C -H
6
); 5b: l 8.30 (1H, s,
17. Woerner, F. P.; Reimlinger, H. A. Chem. Ber. 1970, 103,
5
4
C -H
6
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); 5c: l 7.79 (1H, s, C -H);
6
1908.
5
4
5