1,3-Dipolar cycloadditions of MeOPEG-bounded azides

Article abstract of DOI:10.1016/j.tet.2005.03.049

1,3-Dipolar cycloadditions of MeOPEG-supported azide 2 with a variety of dipolarophiles have been studied. 1-MeOPEG-supported 1,2,3-triazoles 4 and 5, 1,2,3,4-tetrazoles 12 and aziridine 14 were obtained in nearly quantitative yields. The removal of the MeOPEG moiety from the 1,2,3-triazole nucleus was achieved by acidic cleavage of the cycloadduct mixtures 4 and 5 giving 4- and 5-substituted-1,2,3-triazoles 6 and 7.

Full text of DOI:10.1016/j.tet.2005.03.049

Tetrahedron 61 (2005) 4983–4987
1,3-Dipolar cycloadditions of MeOPEG-bounded azides
*
Giorgio Molteni and Paola Del Buttero
`
Dipartimento di Chimica Organica e Industriale, Universita degli Studi di Milano, via Golgi 19, 20133 Milano, Italy
Received 20 December 2004; revised 25 February 2005; accepted 10 March 2005
Available online 7 April 2005
Abstract—1,3-Dipolar cycloadditions of MeOPEG-supported azide 2 with a variety of dipolarophiles have been studied. 1-MeOPEG-
supported 1,2,3-triazoles 4 and 5, 1,2,3,4-tetrazoles 12 and aziridine 14 were obtained in nearly quantitative yields. The removal of the
MeOPEG moiety from the 1,2,3-triazole nucleus was achieved by acidic cleavage of the cycloadduct mixtures 4 and 5 giving 4- and
5-substituted-1,2,3-triazoles 6 and 7.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
solid-supported synthesis. Thus, after having demonstrated
the feasibility of poly(ethylene glycol)-supported azide
(MeOPEG-supported azide) cycloadditions towards acetyl-
enic dipolarophiles,13 we present here a systematic study on
the behaviour of these kind of azides towards acetylenes,
ethylenes and the cyano group as dipolarophiles.
1,3-Dipolar cycloaddition between organic azides and a
variety of unsaturated derivatives represent a versatile
method for the direct synthesis of substituted azoles.1
Recently, it have been recognised that 1,2,3-triazoles, which
are formed via azide-acetylene cycloaddition2 are the ideal
representative of ‘click chemistry’.3 Furthermore, a number
of examples are concerned with the synthesis of the 1,2,3,4-
tetrazole ring by azide cycloaddition onto the cyano group.4
Due to their biological activity as anti-HIV5 and anti-
microbial6 agents, as well as selective b3 adrenergic
receptor agonist,7 new methods for the regio- and/or
stereoselective synthesis of both 1,2,3-triazoles and
1,2,3,4-tetrazoles should be highly valuable. In this context,
the two following points should be considered: (i) the
polymer-supported synthesis of small heterocyclic mole-
cules is the subject of intense research activity,8 since it
represent one of the most promising ways to generate small
molecular libraries in the field of combinatorial chemistry,9
(ii) very few examples of cycloaddition reactions involving
resin-bounded azides to acetylenes have been reported,10,11
while no examples are available onto the ethylenic
dipolarophile or the cyano group. In the above-mentioned
papers, however, the azide was prepared using Merri-
field’s,10a polystyrene10b or Wang’s11 resin. These are
insoluble in organic media. Recently, soluble polymers
have gained popularity amongst organic chemists due to
several advantageous features. Analytical simplicity, high
reactivity and low costs of the starting materials actually
compete with that of usual solution chemistry,12 while the
easy reaction work up is one of the major advantages of
2. Results and discussion
First, of all, we devised the monomethylether of poly-
(ethylene glycol) with a MW of 5000 (MeOPEG) as the
suitable soluble support. MeOPEG-supported azide 2 were
easily obtained as previously reported13 from MeOPEG-
mesylate14 (Scheme 1). Heating 2 in dry toluene in the
presence of a large excess (10 mol equiv) of acetylenic
Keywords: Azides; 1,3-Dipolar cycloadditions; Azoles; Polymer-supported
synthesis.
*
Corresponding author. Tel.: C39 02 51314141; fax: C39 02 50314139;
e-mail: giorgio.molteni@unimi.it
Scheme 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.049

4984
G. Molteni, P. Del Buttero / Tetrahedron 61 (2005) 4983–4987
Table 1. Cycloaddition between MeOPEG-supported azide 2 and 1-(1-ethoxy-2-azido)-2-methoxyethane 8 with akynyl dipolarophiles 3
R
Product yield (%)a
Product ratiob
4C5
9
10
4: 5
9: 10
Ph
98
98
96
96
95
97
58
66
49
46
34
30
16
17
26
25
28
24
80:20
83:17
70:30
70:30
57:43
55:45
50:50
80:20
65:35
65:35
55:45
55:45
COOMe
CH2Cl
CH2Br
CH2OH
CH2NH2
a Isolated yields.
b Determined by 1H NMR spectroscopy.
dipolarophile 3 gave the desired MeOPEG-supported-1,2,3-
triazole cycloadducts 4 and 5, as mixture of inseparable
regioisomers. Product yields and ratios are summarised in
Table 1. MeOPEG-supported-1,2,3-triazoles 4 and 5 were
obtained as white solids, in near quantitative yields, simply
by addition of diethyl ether to the crude reaction mixtures.
Structural assignments of the MeOPEG-supported cyclo-
We have also developed the first example of cycloaddition
between MeOPEG-supported azide 2 and a series of
electron-poor (activated) nitriles 11 (Scheme 3). Clean
cycloaddition reactions were performed by heating 2 in dry
toluene in the presence of 20 mol equiv of the appropriate
cyano dipolarophile, while the usual reaction workup gave
MeOPEG-supported-1,2,3,4-tetrazoles 12 in near quanti-
tative yields. Finally, the same protocol using ethyl acrylate
gave the MeOPEG-supported-2-ethoxycarbonyl aziridine
14 (Scheme 3). Structural assignments of the latter product
rely upon 1H NMR spectroscopic analysis, the data obtained
agrees with that of the known 1-benzyl-2-ethoxycarbonyl
aziridine.18 The formation of the MeOPEG-supported
aziridine 14 is not surprising since its formation follows
the known thermal degradative behaviour of the initially-
formed 4,5-dihydro-1,2,3-triazole cycloadduct 13.19
1
adducts rely upon H NMR spectroscopic analysis and are
fully consistent with those of 4- and 5-substituted-1,2,3-
triazoles reported in the literature.15 In particular, the proton
on the C5 of the 1,2,3-triazole ring of 4a-f appears in the
range d 7.79–8.02, thus accounting for the depicted
regiochemistry resulting from cycloaddition. As can be
inferred from Scheme 1, the removal of the MeOPEG
pendant from the mixture of supported cycloadducts 4C5
was accomplished under acidic conditions, affording
1-unsubstituted 1,2,3-triazoles 6 and 7 with 71–85% overall
yield. Finally, the latter products were obtained as pure
regioisomers through silica gel column chromatography.
In order to ensure the effect of the MeOPEG moiety on
regioselectivity, we submitted 1-(1-ethoxy-2-azido)-2-
methoxyethane 816 to a reaction with acetylenic dipolaro-
philes 3 (Scheme 2). The results summarised in Table 1
show that regioselectivity ratio of 1-methoxyethoxy ethyl-
1,2,3-triazoles 9: 10 are generally similar to that observed
for MeOPEG-supported materials and reflect the usual
balance of HOMO and LUMO-dipole control of azide
cycloadditions.17 The only exception to this behaviour
arises with phenylacetylene 3a and may be ascribed to steric
repulsion between the phenyl ring of the dipolarophile and
the MeOPEG residue in the formation of MeOPEG-
supported-5-phenyl-1,2,3-triazole 7a.
Scheme 3.
3. Conclusions
The behaviour of MeOPEG-supported azide 2 towards a
variety of acetylenes, ethylenes and the cyano group as
dipolarophiles illustrates the advantages concerned with
soluble polymer-supported synthesis. All cycloadditions
were satisfactory in terms of product yields and easy workup
procedures. The removal of the MeOPEG pendant was
achieved onto 1,2,3-triazole derivatives 4 and 5, giving
1-unsubstituted-1,2,3-triazoles 6 and 7. As a concluding
remark, the presence of the MeOPEG mojety had little or no
influence on cycloaddition regioselectivity compared with
that of non-polymeric azides.
Scheme 2.

G. Molteni, P. Del Buttero / Tetrahedron 61 (2005) 4983–4987
4985
4. Experimental
CH2Br), 7.84 (1H, s, C5–H); 5d: d 4.60 (2H, t, JZ6.9 Hz,
CH2–N!), 4.67 (2H, s, CH2Br), 7.65 (1H, s, C4–H).
Melting points were measured with a Bu¨chi apparatus in
open capillary tubes and are uncorrected. IR Spectra were
recorded with a Perkin–Elmer 1725X spectrophotometer.
Mass spectra were determined with a VG-70EQ apparatus.
1H NMR and 13C NMR Spectra were taken with a Bruker
AC 300 or AMX 300 instruments in CDCl3 solutions at
room temperature unless otherwise stated. Chemical shifts
are given as ppm from tetramethylsilane, J values are given
in Hz.
4e: d 4.52 (2H, t, JZ7.0 Hz, CH2–N!), 4.73 (2H, s,
CH2OH), 7.97 (1H, s, C5–H); 5e: d 4.56 (2H, t, JZ7.0 Hz,
CH2–N!), 4.67 (2H, s, CH2OH), 7.65 (1H, s, C4–H).
4f: d 4.28 (2H, t, JZ7.4 Hz, CH2NH2), 4.50 (2H, t, JZ
6.9 Hz, CH2–N!), 7.87 (1H, s, C5–H); 5f: d 4.31 (2H, s,
CH2NH2), 4.56 (2H, t, JZ7.0 Hz, CH2–N!), 7.56 (1H, s,
C4–H).
Before use, all MeOPEG-bounded materials were melted at
90 8C at 1 mmHg for 1 h to remove moisture.
4.1.2. MeOPEG-supported 1,2,3,4-tetrazoles 12. A solu-
tion of 2 (5.00 g, 1.0 mmol) and the appropriate nitrile 11
(20.0 mmol) in dry toluene (40 mL) was heated to 90 8C for
48 h. The solvent was partly removed under reduced
pressure and Et2O (40 mL) was added. The white solid
was collected by filtration giving the MeOPEG-supported
cycloadducts 12.
Compounds 6a,20 6b,21 6c,22 6e,23 6f24 and 7a,20 7b25 are
known in the literature. MeOPEG-azide 212 and 1-(1-
ethoxy-2-azido)-2-methoxyethane 816 was synthesised
according to literature procedures.
1
4.1. Yields and H NMR purity determination of
MeOPEG-bounded compounds
12a (4.76 g, 92%). dH 3.25 (2H, t, JZ7.0 Hz, CH3OCH2–),
3.34 (3H, s, CH3OCH2–), 4.54 (2H, t, JZ7.0 Hz, –CH2–
N!), 7.50–7.75 (5H, aromatics).
The yields of MeOPEG-bounded materials were determined
by weight of pure compounds. It was assumed that the
average MW of MeOPEG monomethylether residue is
5000 Da, while the MW actually encompasses the range
between 4500 and 5500 Da. The purity of MeOPEG-
bounded compounds were determined by 1H NMR analyses
with pre-saturation of the MeOPEG methylene signals at d
3.64. In order to ensure complete relaxation of the proton
nuclei and integration accuracy, we set relaxation delay
(RD) to 6 s and aquisition time (AQ) to 4 s. The integrations
of the PEG fragment CH3OCH2, which were found between
d 3.30 and 3.37, were used as internal standards with an
estimated integration error of G4%.
12b (4.96 g, 95%). dH 1.46 (3H, t, JZ6.6 Hz, CH3–
CH2OCO), 3.25 (2H, t, JZ7.0 Hz, CH3OCH2–), 3.34 (3H,
s, CH3OCH2–), 4.26 (2H, q, JZ6.6 Hz, CH3–CH2OCO),
4.56 (2H, t, JZ7.0 Hz, –CH2–N!).
12c (4.88 g, 96%). dH 3.25 (2H, t, JZ7.0 Hz, CH3OCH2–),
3.34 (3H, s, CH3OCH2–), 4.35 (2H, s, Ph-CH2OCO), 4.56
(2H, t, JZ7.0 Hz, –CH2–N!), 7.10–7.60 (5H, aromatics).
12d (4.99 g, 95%). dH 2.38 (3H, s, CH3–C6H4), 3.25 (2H, t,
JZ7.0 Hz, CH3OCH2–), 3.34 (3H, s, CH3OCH2–), 4.58
(2H, t, JZ7.0 Hz, –CH2–N!), 7.50–8.00 (4H, aromatics).
4.1.1. MeOPEG-supported 1,2,3-triazoles 4 and 5.
A solution of 2 (5.00 g, 1.0 mmol) and the appropriate
alkynyl derivative 3 (10.0 mmol) in dry toluene (40 mL)
was heated to 70 8C for 48 h. The solvent was partly
removed under reduced pressure and Et2O (40 mL) was
added. The white solid was collected by filtration affording
a mixture of the MeOPEG-supported cycloadducts 4C5
(see Table 1 for yields and yield ratio).
4.1.3. MeOPEG-supported 2-ethoxycarbonylaziridine
14. A solution of 2 (5.00 g, 1.0 mmol) and ethyl acrylate
(2.00 g, 20.0 mmol) in dry toluene (40 mL) was heated to
70 8C for 16 h. The solvent was partly removed under
reduced pressure and Et2O (40 mL) was added. The white
solid was collected by filtration giving the MeOPEG-
supported aziridine 14 (4.45 g, 87%) d 1.24 (3H, t, JZ
7.1 Hz, CH3CH2O–), 1.51 (1H, dd, JZ3.3, 1.3 Hz, –HCH–),
2.07 (1H, dd, JZ6.7, 3.3 Hz, –HCCOOEt), 2.23 (1H, dd,
JZ6.7, 1.3 Hz, –HCH–), 3.30 (3H, s, CH3OCH2–), 3.35
(2H, t, JZ7.0 Hz, CH3OCH2–), 4.11 (2H, q, JZ7.1 Hz,
CH3CH2O–).
The following data are selected from the 1H NMR analyses
of the mixtures 5C6 in CDCl3 solutions; signals due to the
PEG fragment CH3OCH2 have been omitted.
4a: d 4.53 (2H, t, JZ7.0 Hz, CH2–N!), 7.20–7.40 (4H, m,
aromatics), 7.97 (1H, s, C5–H); 5a: d 4.47 (2H, t, JZ7.0 Hz,
CH2–N!), 7.20–7.40 (4H, aromatics), 7.65 (1H, s, C4–H).
4.1.4. 1-H-1,2,3-Triazoles 6 and 7. A solution of 4C5
(7.50 g) in chloroform (4.5 mL) and 95% formic acid
(4.5 mL) was stirred at room temperature for 1 h, and then
refluxed for 6 h. Et2O (40 mL) was added and the white
solid was filtered off. The solvent was partly evaporated
under reduced pressure, chloroform (20 mL) was added and
the mixture was washed firstly with water (2!10 mL), then
with 5% aqueous sodium hydrogencarbonate (2!10 mL).
The organic layer was dried over sodium sulfate, the solvent
was evaporated and the residue was chromatographed on a
silica gel column with ethyl acetate/dichloromethane 4:1
affording 1-H-1,2,3-triazoles 6 and 7.
4b: d 3.93 (3H, s, COOCH3), 4.54 (2H, t, JZ7.0 Hz, CH2–
N!), 8.02 (1H, s, C5–H); 5b: d 3.90 (3H, s, COOCH3), 4.90
(2H, t, JZ7.0 Hz, CH2–N!), 7.65 (1H, s, C4–H).
4c: d 4.45 (2H, t, JZ6.9 Hz, CH2–N!), 4.67 (2H, s,
CH2Cl), 7.79 (1H, s, C5–H); 5c: d 4.56 (2H, t, JZ6.9 Hz,
CH2–N!), 4.74 (2H, s, CH2Cl), 7.58 (1H, s, C4–H).
4d: d 4.53 (2H, t, JZ6.9 Hz, CH2–N!), 4.58 (2H, s,

4986
G. Molteni, P. Del Buttero / Tetrahedron 61 (2005) 4983–4987
6a (0.11 g, 42%).
9b (0.38 g, 66%) as pale yellow thick oil. 1H NMR d 3.30–
3.70 (8H, m), 3.78 (3H, s), 3.93 (3H, s), 8.11 (1H, s); MS m/z
(EI) 229 (MC). Anal. Calcd for C9H15N3O4: C, 47.16; H,
6.60; N, 18.33%). Found: C, 47.11; H, 6.64; N, 18.38.
6b (0.13 g, 68%).
6c (89 mg, 52%).
1
9c (0.27 g, 49%) as colourless thick oil. H NMR d 3.35–
3.70 (10H, m), 3.76 (3H, s), 8.04 (1H, s); MS m/z (EI) 219
(MC). Anal. Calcd for C8H14ClN3O2: C, 43.74; H, 6.42; N,
19.13%). Found: C, 43.79; H, 6.38; N, 19.18.
6d (0.12 g, 52%) as white solid mp 64 8C (from diisopropyl
1
ether). H NMR (DMSO-d6) d 3.64 (2H, s), 8.37 (1H, s),
11.12 (1H, br s); 13C NMR (DMSO-d6) d 37.4 (t), 127.85
(d), 128.50 (s); MS m/z (EI) 162 (MC). Anal. Calcd for
C3H4BrN3: C, 22.24; H, 2.49; N, 25.94%. Found: C, 22.29;
H, 2.54; N, 26.04.
9d (0.30 g, 46%) as pale yellow thick oil. 1H NMR d 3.40–
3.80 (10H, m), 3.92 (3H, s), 7.96 (1H, s); MS m/z (EI) 264
(MC). Anal. Calcd for C8H14BrN3O2: C, 36.38; H, 5.34; N,
15.91%. Found: C, 36.43; H, 5.38; N, 15.98.
6e (68 mg, 47%).
1
9e (0.17 g, 34%) as colourless thick oil. H NMR d 2.90
6f (55 mg, 39%).
(1H, br s), 3.44–3.80 (10H, m), 3.90 (3H, s), 8.11 (1H, s);
MS m/z (EI) 201 (MC). Anal. Calcd for C8H15N3O3: C,
47.75; H, 7.51; N, 20.88%. Found: C, 47.71; H, 7.47; N,
20.95.
7a (0.11 g, 42%).
7b (27 mg, 17%).
1
9f (0.15 g, 30%) as colourless thick oil. H NMR d 3.12–
3.85 (12H, m), 3.94 (3H, s), 7.91 (1H, s); MS m/z (EI) 200
(MC). Anal. Calcd for C8H16N4O2: C, 47.99; H, 8.05; N,
27.98%. Found: C, 48.03; H, 8.09; N, 28.04.
7c (48 mg, 28%) as white solid mp 57 8C (from diisopropyl
1
ether). H NMR (DMSO-d6) d 3.76 (2H, s), 7.89 (1H, s),
11.05 (1H, br s); 13C NMR (DMSO-d6) d 43.74 (t), 126.15
(s), 129.13 (d); MS m/z (EI) 117 (MC). Anal. Calcd for
C3H4ClN3: C, 30.66; H, 3.43; N, 35.75%. Found: C, 30.61;
H, 3.47; N, 35.82.
10a (0.10 g, 16%) as colourless thick oil. 1H NMR d 3.40–
3.80 (8H, m), 3.82 (3H, s), 7.0–7.3 (5H, m), 7.69 (1H, s);
MS m/z (EI) 247 (MC). Anal. Calcd for C13H17N3O2: C,
63.14; H, 6.30; N, 16.99%. Found: C, 63.11; H, 6.25; N,
16.93.
1
7d (66 mg, 28%) as yellow thick oil. H NMR (DMSO-d6)
d 3.66 (2H, s), 7.83 (1H, s), 11.15 (1H, br s); 13C NMR
(DMSO-d6) d 37.9 (t), 126.00 (s), 128.88 (d); MS m/z (EI)
162 (MC). Anal. Calcd for C3H4BrN3: C, 22.24; H, 2.49; N,
25.94%. Found: C, 22.21; H, 2.54; N, 25.93.
10b (95 mg, 17%) as pale yellow thick oil. 1H NMR d 3.30–
3.75 (8H, m), 3.78 (3H, s), 3.95 (3H, s), 7.65 (1H, s); MS m/z
(EI) 229 (MC). Anal. Calcd for C9H15N3O4: C, 47.16; H,
6.60; N, 18.33%. Found: C, 47.20; H, 6.65; N, 18.40.
7e (56 mg, 38%) as colourless thick oil. IR (nujol)
1
3385 cmK1; H NMR (DMSO-d6) d 2.80 (1H, br s), 3.90
(2H, s), 7.90 (1H, s), 10.90 (1H, br s); 13C NMR (DMSO-d6)
d 54.74 (t), 125.90 (s), 128.76 (d); MS m/z (EI) 99 (MC).
Anal. Calcd for C3H5N3O: C, 36.36; H, 5.09; N, 42.41%.
Found: C, 36.40; H, 5.12; N, 42.47.
1
10c (0.14 g, 26%) as colourless thick oil. H NMR d 3.35–
3.78 (10H, m), 3.88 (3H, s), 7.51 (1H, s); MS m/z (EI) 219
(MC). Anal. Calcd for C8H14ClN3O2: C, 43.74; H, 6.42; N,
19.13%. Found: C, 43.79; H, 6.38; N, 19.18.
7f (45 mg, 32%) as colourless thick oil. IR (nujol) 3280,
10d (0.16 g, 25%) as pale yellow thick oil. 1H NMR d 3.40–
3.80 (10H, m), 3.90 (3H, s), 7.58 (1H, s); MS m/z (EI) 264
(MC). Anal. Calcd for C8H14BrN3O2: C, 36.38; H, 5.34; N,
15.91%. Found: C, 36.42; H, 5.31; N, 15.86.
1
3160 cmK1; H NMR (DMSO-d6) d 2.24 (2H, br s), 3.16
(2H, s), 7.81 (1H, s), 10.86 (1H, br s); 13C NMR (DMSO-d6)
d 46.26 (t), 126.16 (s), 129.10 (d); MS m/z (EI) 98 (MC).
Anal. Calcd for C3H6N4: C, 36.73; H, 6.16; N, 57.11%.
Found: C, 36.78; H, 6.20; N, 57.17.
1
10e (0.14 g, 28%) as colourless thick oil. H NMR d 2.80
(1H, br s), 3.40–3.85 (10H, m), 3.90 (3H, s), 7.61 (1H, s);
MS m/z (EI) 201 (MC). Anal. Calcd for C8H15N3O3: C,
47.75; H, 7.51; N, 20.88%. Found: C, 47.80; H, 7.52; N,
20.94.
4.1.5. Dipolar cycloaddition between 1-(1-ethoxy-2-
azido)-2-methoxyethane 8 and acetylenes 3. A solution
of 8 (0.36 g, 2.5 mmol) and the appropriate alkynyl
derivative 3 (10.0 mmol) in dry toluene (25 mL) was heated
to 65 8C for 48 h. The solvent was removed under reduced
pressure and the residue was chromatographed on a silica
gel column with ethyl acetate/hexane 2:1 affording 1,2,3-
triazoles 9 and 10.
1
10f (0.12 g, 24%) as colourless thick oil. H NMR d 3.10–
3.85 (12H, m), 3.90 (3H, s), 7. 95 (1H, s); MS m/z (EI) 200
(MC). Anal. Calcd for C8H16N4O2: C, 47.99; H, 8.05; N,
27.98%. Found: C, 48.01; H, 8.03; N, 27.94
1
9a (0.36 g, 58%) as colourless thick oil. H NMR d 3.38–
3.75 (8H, m), 3.80 (3H, s), 7.0–7.3 (5H, m), 8.07 (1H, s);
MS m/z (EI) 247 (MC). Anal. Calcd for C13H17N3O2: C,
63.14; H, 6.30; N, 16.99%. Found: C, 63.19; H, 6.27; N,
17.05.
Acknowledgements
Thanks are due to MURST and CNR for financial support.
We thank the NMR specialist Dr. Lara De Benassuti,

G. Molteni, P. Del Buttero / Tetrahedron 61 (2005) 4983–4987
4987
University of Milan, for 1H NMR analyses of the MeOPEG-
supported materials. G. M. is grateful to Professor Luisa
Garanti for valuable suggestions and comments.
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