Synthesis of macrocycles containing 1,2,3-triazole motifs

Article abstract of DOI:10.1055/s-0031-1290760

A new procedure for the preparation of macrocycles containing 1,2,3-triazole motifs is developed. The macrocyclic precursor is constructed by repetition of a series of steps which include cycloaddition of an azide with an alkyne, alkylation of a carboxylic acid with propargyl bromide and formation of an azide from an amino group. The order of the steps and the size of the connected fragments are determined by the desired ring size. Chromatographic purification techniques for the poorly soluble final products are also described. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290760

1398▌
PAPER
paper
Synthesis of Macrocycles Containing 1,2,3-Triazole Motifs
Macrocycles Containing 1,2,3-Triazole Motifs
Ludmila Hradilová,a Martin Grepl,a,b Jan Hlaváč,a Antonín Lyčka,c,d Pavel Hradil*a,b
a
Department of Organic Chemistry, Palacky University, Tr. 17. Listopadu 12, 771 46 Olomouc, Czech Republic
b
Farmak a.s., Na Vlcinci 3, 771 17 Olomouc, Czech Republic
Fax +420(58)231424; E-Mail: hradil@farmak.cz
c
Research Institute for Organic Syntheses, Rybitvi 296, 533 54 Pardubice, Czech Republic
d
University of Hradec Kralove, Faculty of Science, Rokitanského 62, 500 03 Hradec Králove 3, Czech Republic
Received: 15.01.2012; Accepted after revision: 17.02.2012
macrocyclic unit.7–12 This strategy has been well docu-
mented in a review article.13
Abstract: A new procedure for the preparation of macrocycles con-
taining 1,2,3-triazole motifs is developed. The macrocyclic precur-
sor is constructed by repetition of a series of steps which include
cycloaddition of an azide with an alkyne, alkylation of a carboxylic
acid with propargyl bromide and formation of an azide from an ami-
no group. The order of the steps and the size of the connected frag-
ments are determined by the desired ring size. Chromatographic
purification techniques for the poorly soluble final products are also
described.
The formation of macrocycle 4, which contains a 16-
membered ring, was observed during the preparation of
4H,6H-[1,2,3]triazolo[1,5-a][4,1]benzoxazepin-6-one
derivatives.14,15 The spontaneous dimerization of propar-
gyl azidobenzoate 2 into dimer 3 requires a very long re-
action time. The method employed for the cyclization of
dimer 3 is useful for the preparation of macrocycle 4, but
it is not appropriate for the synthesis of molecules con-
taining a larger ring system (Scheme 1).14
Key words: macrocycles, 1,2,3-triazole, cycloaddition, azidoben-
zoate, propargyl ester
Based on our previous experience in this field,14 we decid-
ed to develop a general method for the preparation of tri-
azole-containing macrocycles of this type with various
ring sizes.
Numerous naturally occurring macrocyclic molecules are
known, with examples comprising porphyrins, cyclopep-
tides and cyclic diterpenes. Some of these compounds dis-
play remarkable biological activity, and many of them (or
their derivatives) are used as drugs.1,2 Several other class-
es of macrocyclic compounds, including cyclophanes,
crown ethers and glycophanes, are synthesized primarily
in the laboratory.
The stepwise construction of the macrocycles was found
to be a suitable strategy, and compound 4 was selected as
the initial target. 2-Azidobenzoic acid (6) was used as the
starting material and was itself prepared according to a
previously described procedure.16 This azido derivative
was coupled with propargyl anthranilate (1),14 and alkyla-
tion of the resulting carboxylic acid 7 with propargyl bro-
mide yielded ester 8. This ester was then transformed into
azido derivative 3 via the diazonium salt. Compound 3 un-
derwent cycloaddition to afford macrocycle 4, as de-
scribed previously14 (Scheme 2). Azido derivative 3 and
macrocycle 4 were compared with the previously pre-
pared compounds and showed identical melting points,
NMR spectra and high-resolution mass spectrometric
data.
Macrocycles containing a heterocyclic ring system pos-
sess a favorable binding site for metal ions3 and can poten-
tially act as molecular hosts.4 Cyclophanes with triazole
rings might be expected to exhibit increased complexing,
chelating and solubilizing abilities due to the presence of
a greater number of heteroatoms.5 Macrocyclic com-
pounds possessing triazole rings have been applied as op-
tical and electrochemical chemosensors.6 Intramolecular
dipolar cycloaddition between azides and alkynes is a
commonly used method for the synthesis of various mac-
rocycles in which the 1,2,3-triazole moiety is a part of the
O
O
2
6
15
10
7
16
8
3
3
10
N
7
1
9
5
1
O
O
N
N
9
8
11
O
O
5
4
14
N
N
6
2
6
N
O
O
4
12
5
13
N3
3
N
7
9
4
O
O
2
17
NH2
N3
1
N
O
8
N
18
19
O
1
2
3
10
20
4
Scheme 1 Original preparation of macrocycle 4
SYNTHESIS 2012, 44, 1398–1404
Advanced online publication: 29.03.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1290760; Art ID: SS-2012-Z0047-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Macrocycles Containing 1,2,3-Triazole Motifs
1399
O
COOH
NH2
COOH
N3
a
d
O
4
N
N
42%
N
X
ROOC
7 X = NH2, R = H; 87%
5
6
b
c
8 X = NH2, R = propargyl; 84%
3 X = N3, R = propargyl; 94%
Scheme 2 Newly designed synthesis of macrocycle 4. Reagents and conditions: (a) n-BuOH, H2O, CuSO4, ascorbic acid, 1, r.t., 1 h; (b) DMF,
K2CO3, propargyl bromide, r.t.; (c) acetone, HCl, NaNO2, H2O, 0 °C, then NaN3, r.t., 0.5 h; (d) DMF, reflux, 1.5 h.
This experiment verified that it was possible to construct tramolecular dipolar cycloaddition (Scheme 3). Macrocy-
a macrocyclic ring via several consecutive steps. Howev- cles 4, 13 and 17 were produced in moderate yields
er, it was not practical to use the same approach for the ranging from 40–65%. The 1H and 13C NMR spectral data
construction of larger rings because the synthesis would of compounds 4 and 7–17 are collated in Table 1. During
be too long. Therefore, larger structural units were pre- the macrocyclization of derivative 12, a significant
pared in advance by cyclization of key azide 9, itself pre- amount of macrocycle 4 was formed in addition to the ex-
pared from amine 7, with the appropriate propargyl esters pected product 13. The exact mechanism for this particu-
to give 10 or 14. The carboxylic acid group was then al- lar transformation is not known, but it probably involves
kylated to form propargyl ester 11 or 15, and the amino initial formation of macrocycle 13 followed by a trans-
group was transformed into an azide to afford compounds esterification step to form the smaller ring macrocycle 4.
12 or 16. The final macrocyclization was achieved via in-
9
O
10
O
O
8
6
26
21
25
23
10
N
8
9
1
1
8
5
7
7
O
5
3
24
2
N
4
6
2
9
7
5
6
N
N
22
27
4
X
3
N
N
N
1
10
O
2
17
4
N
O
N
e
3
O
COOR
N
O
N
28
13
15
12
16
29
3
O
40
N
38
N
39
O
14
4
5
11
30
36
35
N
31
N
32
O
2
37
33
10
O
N
N
O
N
1
5
3
6
9
7
1
b
N
4
2
O
34
6
8
8
N
7
N
10
14 X = NH2, R = H; 97%
9
c
15 X = NH2, R = propargyl; 91%
16 X = N3, R = propargyl; 65%
17 60–65%
d
COOH
N
N3
N
N
a
7
O
93%
O
9
O
O
10
7
26
25
23
6
3
7
8
10
3
8
9
5
f
1
4
9
1
5
4
21
2
6
O
O
9
N
24
N
8
2
N
N
6
22
27
N
N
7
N
X
1
2
10
i
N
5
O
O
N
O
O
N
29
4
3
N
+
4 30–45%
3
N
28
N
O
4
O
N
N
30
16
15
2
17
11
5
RO
6
O
1
12
13
7
10
8
9
14
10 X = NH2, R = H; 89%
13 40–46%
g
11 X = NH2, R = propargyl; 84%
12 X = N3, R = propargyl; 57%
h
Scheme 3 Synthesis of macrocycles 4, 13 and 17. Reagents and conditions: (a) acetone, HCl, NaNO2, H2O, 0 °C, then NaN3, r.t., 0.5 h; (b)
DMF, 8, ascorbic acid, CuSO4, H2O, r.t.; (c) DMF, K2CO3, propargyl bromide, r.t.; (d) acetone, HCl, NaNO2, H2O, 0 °C, then NaN3, r.t., 0.5 h;
(e) DMF, reflux, or DMF, ascorbic acid, CuSO4, H2O, r.t., 0.5 h; (f) DMF, 1, ascorbic acid, CuSO4, H2O, r.t.; (g) DMF, K2CO3, propargyl bro-
mide, r.t.; (h) acetone, HCl, NaNO2, H2O, 0 °C, then NaN3, r.t., 0.5 h; (i) DMF, reflux, or DMF, ascorbic acid, CuSO4, H2O, r.t.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1398–1404

1400
L. Hradilová et al.
PAPER
Table 1 1H and 13C NMR Spectral Data (δ, ppm, DMSO-d6) for Compounds 4 and 7–17
Product Position
1
2
3
4
5
6
7
8
9
10
11
7a
Amine
δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
–
–
6.84
116.6
6.83
116.7
6.83
116.7
6.84
116.6
6.82
116.6
6.83
116.6
7.47
120.9
7.45
120.8
7.45
120.8
7.65
127.3
7.67
126.1
7.67
126.1
14
7.31
134.4
7.30
134.4
7.28
134.4
7.31
134.4
7.29
134.4
7.29
134.4
7.71
133.8
7.68
133.8
7.68
133.8
7.90
133.7
7.89
133.5
7.82
133.3
15
6.57
114.9
6.55
114.9
6.52
114.9
6.57
114.9
6.54
114.9
6.55
114.9
7.33
125.1
7.30
125.0
7.30
125.0
7.84
130.6
7.81
130.5
7.73
130.6
16
7.77
130.9
7.72
130.9
7.72
130.9
7.77
130.9
7.78
130.9
7.76
130.9
7.85
131.3
7.85
130.8
7.85
130.8
8.15
131.5
8.11
131.0
7.94
130.9
17
–
5.47
57.1
5.44
57.2
5.43
57.2
5.49
57.1
5.43
57.1
5.43
57.1
5.52
58.1
5.46
58.0
5.46
58.0
5.22
58.1
5.23
58.5
5.24
58.5
19
–
8.74
126.3
8.71
126.2
8.74
126.2
8.74
126.3
8.72
126.2
8.72
126.1
8.75
126.5
8.74
126.4
8.74
126.4
8.44
127.1
8.37
126.6
8.21
125.8
21
–
108.4
–
151.7
–
167.1
–
142.5
–
135.5
10b
14c
8d
–
108.4
–
151.7
–
167.1
–
142.6
–
135.5
–
108.4
–
151.7
–
167.1
–
142.6
–
135.4
Ester
–
108.4
–
151.7
–
167.1
–
142.5
–
135.5
11e
15f
9
–
108.4
–
151.6
–
167.0
–
142.6
–
135.4
–
108.4
–
151.6
–
167.1
–
142.6
–
135.4
Azide
–
122.2
–
139.2
–
164.4
–
141.8
–
135.3
12
16
4
–
122.1
–
139.2
–
164.2
–
142.1
–
135.4
–
121.1
–
139.2
–
164.2
–
142.1
–
135.4
Macro-
cycle
–
127.0
–
135.5
–
165.0
–
141.4
–
–
13
17
–
127.0
–
134.9
–
165.1
–
141.7
–
–
–
126.7
12
134.9
13
165.1
18
141.4
20
–
Product Position
22
7a
Amine
δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
–
8.03
130.8
8.03
7.79
130.3
7.78
7.90
133.5
7.80
7.76
126.8
7.76
–
–
–
–
–
–
126.5
–
164.3
–
–
–
–
–
–
10b
14c
8d
–
–
–
–
–
127.0
–
130.8
130.3
133.4
126.8
166.6
–
–
–
–
–
–
g
h
i
j
–
–
–
–
–
g
h
i
j
126.9
–
164.7
–
–
–
–
135.4
–
126.2
Ester
8.03
130.8
8.05
7.79
130.3
7.77
7.90
133.5
7.88
7.76
126.8
7.77
4.79
53.0
4.79
53.0
4.79
53.0
–
3.59
77.6
3.60
77.7
3.59
77.7
–
126.5
–
164.3
–
78.3
–
–
–
11e
15f
–
–
126.4
–
130.8
130.4
133.4
126.8
164.2
–
78.3
–
133.4
–
126.9
–
l
m
n
o
l
m
n
o
126.3
164.2
78.3
135.4
126.9
Synthesis 2012, 44, 1398–1404
© Georg Thieme Verlag Stuttgart · New York

PAPER
Macrocycles Containing 1,2,3-Triazole Motifs
1401
Table 1 1H and 13C NMR Spectral Data (δ, ppm, DMSO-d6) for Compounds 4 and 7–17
Product Position
12
13
14
15
16
17
18
19
20
21
22
–
Azide
9
δH
δC
δH
δC
δH
δC
–
8.00
130.6
8.05
7.73
130.2
7.78
7.81
132.6
7.89
7.69
126.7
7.76
–
–
–
–
–
128.7
–
–
–
–
–
–
–
12
16
–
4.79
53.0
4.77
53.0
29
–
3.60
77.6
3.59
77.7
31
–
–
126.4
–
130.8
130.3
133.5
126.8
164.4
–
78.3
–
135.4
126.9
q
r
s
t
–
–
q
r
s
t
126.9
23
164.2
28
78.3
30
–
–
Product Position
24
25
26
27
32
33
–
10b
14c
11e
15f
Amine
Ester
δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
δH
δC
8.03
7.78
7.80
7.76
–
–
–
–
–
–
130.8
130.3
133.4
126.8
166.6
–
–
–
–
–
–
–
g
h
i
j
g,k
5.28
58.5
5.36
58.3
5.35
58.3
5.34
58.2
5.46
58.2
–
8.38
126.6
8.55
126.4
8.55
126.3
8.64
126.4
8.74
126.4
–
–
g
h
i
j
g,k
164.7
–
141.5
–
135.4
–
126.9
8.02
7.88
7.88
7.77
–
–
130.8
130.3
133.4
126.8
164.7
–
141.5
–
–
–
–
l
m
n
o
l,p
–
–
l
m
n
o
l,p
164.7
–
141.5
–
135.4
–
126.9
Azide 12
8.01
7.76
7.89
7.76
–
–
130.8
130.2
134.4
126.8
164.7
–
141.5
–
–
–
–
q
r
s
t
q,u
16
–
–
q
r
s
t
q,u
164.2
142.1
135.4
126.9
a δH 6.76 (NH2).
b δH 6.74 (NH2).
c δH 6.76 (NH2).
d δH 6.76 (NH2).
e δH 6.74 (NH2).
f δH 6.74 (NH2).
g δH 8.01–8.05, δC 2 × 130.84, 130.82.
h δH 7.74–7.78, δC 130.34, 130.29 or 130.27 [+ C(34)H].
i δH 7.80–7.88, δC 2 × 133.35, 133.32 [+ C(35)H].
j δH 7.74–7.78, δC 126.78, 126.75 or 126.67 [+ C(36)H].
k δH –, δC 164.7 (37); δH 5.31, δC 58.3 (38); δH –, δC 141.3 (39); δH 8.54, δC 126.5 (40).
l δH 8.01–8.06, δC 130.83, 130.81 or 130.74.
m δH 7.73–7.79, δC 130.35, 130.29, 130.21 [+ C(34)H].
n δH 7.84–7.94, δC 133.54, 133.33 or 133.31 [+ C(35)H].
o δH 7.73–7.79, δC 126.81, 126.71 or 126.68 [+ C(36)H].
p δH –, δC 164.7 (37); δH 5.31, δC 58.3 (38); δH –, δC 141.5 (39); δH 8.53, δC 126.3 (40).
q δH 8.00–8.04, δC 130.80, 130.36, 130.27.
r δH 7.73–7.79, δC 130.35, 130.29 or 130.25 [+ C(34)H].
s δH 7.82–7.90, δC 133.82, 133.56 or 133.34 [+ C(35)H].
t δH 7.73–7.78, δC 126.86, 126.84, 126.82 [+ C(36)H].
u δH –, δC 164.2 (37); δH 5.46, δC 58.2 (38); δH –, δC 142.1 (39); δH 8.74, δC 126.4 (40).
Purification of the prepared macrocycles was problematic products was to prepare solutions of the macrocycles in
as their solubility in organic solvents was quite low. For acetic acid or acetic acid containing hydrochloric acid and
example, they were found to precipitate from hot N,N-di- then to purify the solution by column chromatography. A
methylformamide. The best method found to purify the detailed purification procedure is described below.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1398–1404

1402
L. Hradilová et al.
PAPER
Cycloaddition; General Procedure (GP 3B)
The major contribution of the article is the new method
that makes it possible to synthesize these macrocycles
from simple compounds such as 2-azidobenzoic acid,
propargyl bromide and propargyl anthranilate through se-
quential steps. These macrocycles may be interesting ow-
ing to their ability to form very strong complexes with
metals.
Azido derivative 12 or 16 (2.5 mmol), or a mixture of azido deriva-
tive 6 or 9 (2.5 mmol) and propargyl derivative 1 or 8 (2.5 mmol)
was dissolved in DMF (25 mL). A soln of ascorbic acid (0.15 g,
0.85 mmol) in H2O (2.5 mL) and a soln of CuSO4 (0.09 g, 0.36
mmol) in H2O (2.5 mL) were added, and the mixture was stirred at
r.t. until the starting material had been consumed (ca. 30 min) (TLC,
toluene–EtOAc–HCO2H, 25:25:1). The soln was poured into a mix-
ture of H2O (200 mL) and ice (50 g) and the resulting solid precip-
itate was filtered, washed with H2O and purified by column
chromatography on silica gel (EtOAc).
Analytical TLC was performed on DC-Fertigfolien Polygram Sil
G/UV254 plates from Macherey-Nagel. The products were purified
by column chromatography on Silia Flash P60 230–400 mesh silica
gel from company Silicycle. Melting points were recorded on a
Köfler apparatus and are uncorrected. IR spectra were recorded
with a Nicolet iS10 FT-IR spectrometer. 1H and 13C NMR spectra
were recorded on a Bruker Avance spectrometer (500.13 MHz for
1H, 125.76 MHz for 13C) and on a Bruker Avance II 400 spectrom-
eter (400.13 MHz for 1H, 100.56 MHz for 13C) in DMSO-d6. The 1H
and 13C chemical shifts were referenced to TMS as the internal stan-
dard (δ = 0.0). All 2D experiments [gradient-selected (gs)-COSY,
NOESY, gs-HMQC, gs-HMBC] were performed using Topspin 2.1
software. The numbering of carbons for NMR purposes is shown in
Schemes 1 and 3. The numbering of the propargyl group is shown
in Scheme 1. HRMS was performed on a Thermo Exactive (Orbi-
trap) instrument under ESI-MS conditions. All azides, especially 12
and 16, have limited stability and must be used for another step as
soon as possible. Petroleum ether (PE) refers to the fraction boiling
in the 30–70 °C range. CAUTION: Although no problems were ob-
served while handling the azido derivatives, these compounds may
be explosive and are potentially dangerous!
Chromatographic Purification of the Macrocycles; General
Procedure (GP 4)
The dried solid compound was dissolved in AcOH. If the product
was insoluble in AcOH then it was instead dissolved in a minimal
amount of a mixture of concd HCl–AcOH (15:85). This soln was
separated on a silica gel column. The column was first eluted with
toluene–EtOAc–HCO2H (25:25:1) to remove unidentified impuri-
ties. The macrocyclic products were then gradually eluted with a
mixture of EtOAc–HCO2H (50:1). The fractions containing the
product were separated and concentrated to dryness. The solid prod-
uct was then stirred in a 5% aq soln of (NH4)2CO3, filtered, washed
with H2O and dried to a constant weight.
Prop-2-yn-1-yl 2-(4-{[(2-Azidophenyl)carbonyloxy]methyl}-
1H-1,2,3-triazol-1-yl)benzoate (3)
Azide 3 was prepared from 8 according to GP 2.
IR (neat, ATR): 3203, 2122, 2089, 1726, 1707, 1600, 1448, 1258,
1087, 1049, 775, 774 cm–1.
Yield: 0.95 g (94%); white solid; mp 126–129 °C (Lit.14 mp 131–
133 °C).
Propargylation of Carboxylic Acids; General Procedure (GP 1)
To a soln of carboxylic acid 7, 10 or 14 (6 mmol) in DMF (30 mL)
was added K2CO3 (0.83 g, 6 mmol) and the mixture heated at reflux
temperature for 5 min. After cooling to r.t., 80% propargyl bromide
(0.89 g, 6 mmol) was added and the resulting mixture was stirred at
the same temperature. Following complete consumption of the
starting material (TLC, toluene–EtOAc–HCO2H, 25:25:1), the mix-
ture was filtered, poured into H2O (400 mL) and the precipitated
solid removed by filtration. If an emulsion formed, the mixture was
extracted with EtOAc (3 × 50 mL), and the combined organic layer
separated and evaporated under reduced pressure. The oily residue
was dissolved in EtOH–H2O (6 mL, 1:2) after which PE (20 mL)
was added to the soln. The precipitated solid was isolated by filtra-
tion and washed with H2O and PE.
ESI-HRMS: m/z [M + H]+ calcd for C20H15N6O4: 403.11493; found:
403.11487.
9,22-Dioxa-1,12,13,14,25,26-hexaazapentacyc-
lo[22.2.1.111,14.02,7.015,20]octacosa-
2,4,6,11(28),12,15,17,19,24(27),25-decaene-8,21-dione (4)
Macrocycle 4 was prepared from 3 according to GP 3A. The reac-
tion time was 1.5 h.
Yield: 0.42 g (42%); white solid; mp 328–330 °C (DMF) (Lit.14 mp
328–331 °C).
IR (neat, ATR): 3152, 3114, 1708, 1601, 1505, 1289, 1266, 1241,
1230, 1126, 1044, 833, 767, 710 cm–1.
ESI-HRMS: m/z [M + H]+ calcd for C20H15N6O4: 403.11493; found:
403.11465.
Azido Derivatives; General Procedure (GP 2)
Amino derivative 7, 8, 11 or 15 (2.5 mmol) was dissolved in acetone
(20 mL) and treated with concd HCl (1 mL). The resulting mixture
was cooled below 0 °C after which a soln of NaNO2 (0.18 g, 2.6
mmol) in H2O (3 mL) was added. The mixture was stirred for 5 min,
and then a soln of NaN3 (0.17 g, 2.6 mmol) in H2O (3 mL) was add-
ed dropwise at the same temperature. The resulting mixture was
stirred at r.t. until no starting material remained (ca. 30 min) (TLC,
toluene–EtOAc–HCO2H, 25:25:1), and was then poured into H2O
(50 mL). The precipitated crystalline material was filtered, washed
with H2O and air-dried. If an emulsion formed, the mixture was ex-
tracted with EtOAc (4 × 50 mL), and the combined extracts dried,
concentrated and purified by column chromatography on silica gel
(toluene–EtOAc, 2:1).
2-(4-{[(2-Aminophenyl)carbonyloxy]methyl}-1H-1,2,3-triazol-
1-yl)benzoic Acid (7)
To a soln of 2-azidobenzoic acid (6) (2.30 g, 14.10 mmol) in n-
BuOH (100 mL) was added propargyl anthranilate (1) (2.47 g,
14.10 mmol) followed by ascorbic acid (0.8 g, 4.54 mmol) in H2O
(10 mL) and CuSO4 (0.4 g, 1.6 mmol) in H2O (5 mL). The mixture
was stirred at r.t. until the complete disappearance of the starting
material (ca. 1 h). The extent of reaction was monitored by TLC (n-
hexane–EtOAc–HCO2H, 7:3:0.2). A soln of Na2SO3 (0.5 g, 6.4
mmol) in H2O (10 mL) was added, and the copper sulfide that pre-
cipitated was filtered and washed with EtOAc (10 mL). The aq layer
was separated and extracted with EtOAc (2 × 25 mL). The com-
bined organic layer was concentrated under reduced pressure. The
resulting oily residue was dissolved in a mixture of EtOH (16 mL)
and H2O (34 mL), and then PE (50 mL) was added. After 1 h at r.t.,
the mixture was cooled to 0 °C and the precipitated crystals were
filtered and washed with H2O and PE.
Cycloaddition; General Procedure (GP 3A)
Azido derivative 3, 12 or 16 (2.5 mmol) was dissolved in DMF (40
mL) and the mixture heated at reflux temperature until the starting
material had been consumed (TLC, toluene–EtOAc–HCO2H,
25:25:1). The mixture was then poured into H2O (400 mL), and the
precipitated solid was filtered, washed with H2O (3 × 50 mL) and
purified.
Yield: 4.13 g (87%); yellow solid; mp 149–153 °C.
IR (neat, ATR): 3456, 3354, 2922, 2478, 1709, 1682, 1618, 1589,
1487, 1454, 1294, 1238, 1227, 1092, 1067, 1054, 765, 748, 693 cm–1.
Synthesis 2012, 44, 1398–1404
© Georg Thieme Verlag Stuttgart · New York

PAPER
Macrocycles Containing 1,2,3-Triazole Motifs
1403
ESI-HRMS: m/z [M + H]+ calcd for C17H15N4O4: 339.10878; found:
339.10863.
9,22,35-Trioxa-1,12,13,14,25,26,27,38,39-nonaazaheptacyc-
lo[35.2.1.111,14.124,27.02,7.015,20.028,33]dotetraconta-
2,4,6,11(42),12,15,17,19,24(41),25,28(33),29,31,37(40),38-pen-
tadecaene-8,21,34-trione (13) and 9,22-Dioxa-1,12,13,14,25,26-
hexaazapentacyclo[22.2.1.111,14.02,7.015,20]octacosa-
Prop-2-yn-1-yl 2-(4-{[(2-Aminophenyl)carbonyloxy]methyl}-
1H-1,2,3-triazol-1-yl)benzoate (8)
2,4,6,11(28),12,15,17,19,24(27),25-decaene-8,21-dione (4)
Macrocycles 13 and 4 were prepared from 12 according to GP 3A
using a reaction time of 4.5 h. The two major products were sepa-
rated by column chromatography according to GP 4.
Compound 8 was prepared from carboxylic acid 7 according to
GP 1.
Yield: 1.9 g (84%); light-yellow solid; mp 106–109 °C.
IR (neat, ATR): 3441, 3327, 3246, 3116, 2123, 1721, 1684, 1620,
1488, 1373, 1289, 1243, 1162, 1121, 1095, 1052, 757, 705, 693 cm–1.
ESI-HRMS: m/z [M + H]+ calcd for C20H17N4O4: 377.12443; found:
Macrocycle 13
Yield: 0.6 g (40%); white solid; mp 129–133 °C.
IR (neat, ATR): 3143, 3010, 1717, 1603, 1503, 1460, 1381, 1287,
1252, 1122, 1083, 1043, 940, 761, 700 cm–1.
377.12399.
ESI-HRMS: m/z [M + H]+ calcd for C30H22N9O6: 604.16876; found:
604.16875.
2-(4-{[(2-Azidophenyl)carbonyloxy]methyl}-1H-1,2,3-triazol-1-
yl)benzoic Acid (9)
Azide 9 was prepared from 7 according to GP 2. The resulting
emulsion was extracted and the solvent was removed. The residue
was then dissolved in a soln of EtOH and H2O (6 mL, 1:2), and the
title compound was precipitated by the addition of PE.
Macrocycle 4
Yield: 0.45 g (45%).
Macrocycles 13 [0.7 g (46%)] and 4 [0.3 g (30%)] were also pre-
pared by reacting azide 12 (1.5 g, 2.5 mmol) with ascorbic acid
(0.176 g, 1 mmol) and a soln of CuSO4 (0.10 g, 0.40 mmol) in H2O
(2.5 mL) according to GP 3B. The isolated solid was purified by
column chromatography according to GP 4.
Yield 0.85 g (93%); off-white solid; mp 73–76 °C.
IR (neat, ATR): 3145, 2936, 2607, 2137, 2102, 1723, 1578, 1490,
1246, 1232, 1125, 1069, 1052, 833, 762, 749, 693 cm–1.
ESI-HRMS: m/z [M + H]+ calcd for C17H13N6O4: 365.09928; found:
365.09914.
2-{4-[({2-[4-({[2-(4-{[(2-Aminophenyl)carbonyloxy]methyl}-
1H-1,2,3-triazol-1-yl)phenyl]carbonyloxy}methyl)-1H-1,2,3-
triazol-1-yl]phenyl}carbonyloxy)methyl]-1H-1,2,3-triazol-1-
yl}benzoic Acid (14)
Carboxylic acid 14 was prepared from compounds 9 and 8 accord-
ing to GP 3B.
2-[4-({[2-(4-{[(2-Aminophenyl)carbonyloxy]methyl}-1H-1,2,3-
triazol-1-yl)phenyl]carbonyloxy}methyl)-1H-1,2,3-triazol-1-
yl]benzoic Acid (10)
Carboxylic acid 10 was prepared from 9 according to GP 3B.
Yield: 1.2 g (89%); white solid; mp 92–95 °C.
Yield: 1.8 g (97%); ochre solid; mp 110–114 °C.
IR (neat, ATR): 3466, 3369, 3150, 1731, 1683, 1614, 1505, 1290,
1265, 1232, 1163, 1124, 1083, 1047, 824, 793, 761 cm–1.
ESI-HRMS: m/z [M + H]+ calcd for C27H22N7O6: 540.16261; found:
IR (neat, ATR): 3467, 3367, 2961, 1720, 1689, 1616, 1603, 1503,
1456, 1289, 1240, 1122, 1085, 1042, 757, 701 cm–1.
ESI-HRMS: m/z [M + H]+ calcd for C37H29N10O8: 741.21643;
540.16248.
found: 741.21590.
(1-{2-[(Prop-2-yn-1-yloxy)carbonyl]phenyl}-1H-1,2,3-triazol-4-
yl)methyl 2-(4-{[(2-Aminophenyl)carbonyloxy]methyl}-1H-
1,2,3-triazol-1-yl)benzoate (11)
Compound 11 was prepared from carboxylic acid 10 (1.0 g, 1.85
mmol) in DMF (20 mL) according to GP 1. The oily residue was pu-
rified by column chromatography on silica gel (toluene–EtOAc,
3:1).
[1-(2-{[(1-{2-[(Prop-2-yn-1-yloxy)carbonyl]phenyl}-1H-1,2,3-
triazol-4-yl)methoxy]carbonyl}phenyl)-1H-1,2,3-triazol-4-
yl]methyl 2-(4-{[(2-Aminophenyl)carbonyloxy]methyl}-1H-
1,2,3-triazol-1-yl)benzoate (15)
Compound 15 was prepared from carboxylic acid 14 (1.0 g, 1.35
mmol) in DMF (20 mL) according to GP 1.
Yield: 0.96 g (91%); white solid; mp 58–64 °C.
Yield: 0.9 g (84%); ochre solid; mp 81–87 °C.
IR (neat, ATR): 3489, 3145, 1720, 1688, 1616, 1603, 1504, 1289,
1243, 1122, 1083, 1042, 758, 702 cm–1.
ESI-HRMS: m/z [M + H]+ calcd for C40H31N10O8: 779.23208;
IR (neat, ATR): 3476, 3380, 3275, 3147, 2126, 1727, 1683, 1612,
1587, 1505, 1289, 1258, 1232, 1161, 1123, 1086, 1045, 823, 794,
757, 696 cm–1.
ESI-HRMS: m/z [M + H]+ calcd for C30H24N7O6: 578.17826; found:
found: 779.23193.
578.17840.
[1-(2-{[(1-{2-[(Prop-2-yn-1-yloxy)carbonyl]phenyl}-1H-1,2,3-
triazol-4-yl)methoxy]carbonyl}phenyl)-1H-1,2,3-triazol-4-
yl]methyl 2-(4-{[(2-Azidophenyl)carbonyloxy]methyl}-1H-
1,2,3-triazol-1-yl)benzoate (16)
Azide 16 was prepared from 15 according to GP 2. The resulting
emulsion was extracted, the solvent removed and the residue puri-
fied by column chromatography.
(1-{2-[(Prop-2-yn-1-yloxy)carbonyl]phenyl}-1H-1,2,3-triazol-4-
yl)methyl 2-(4-{[(2-Azidophenyl)carbonyloxy]methyl}-1H-
1,2,3-triazol-1-yl)benzoate (12)
Azide 12 was prepared from compound 11 according to GP 2. The
resulting emulsion was extracted, the solvent removed and the resi-
due purified by column chromatography.
Yield: 1.3 g (65%); yellow oil.
Yield: 0.86 g (57%); yellow oil.
IR (neat, ATR): 2983, 2126, 1728, 1603, 1506, 1446, 1372, 1290,
1237, 1123, 1082, 1041, 762, 703 cm–1.
ESI-HRMS: m/z [M + H]+ calcd for C40H29N12O8: 805.22258;
IR (neat, ATR): 2983, 2125, 1728, 1446, 1372, 1290, 1237, 1123,
1081, 1041, 760, 702 cm–1.
ESI-HRMS: m/z [M + H]+ calcd for C30H22N9O6: 604.16876; found:
found: 805.22210.
604.16898.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1398–1404

1404
L. Hradilová et al.
PAPER
9,22,35,48-Tetraoxa-1,12,13,14,25,26,27,38,39,40,51,52-dodeca-
azanonacyclo[48.2.1.111,14.124,27.137,40.02,7.015,20.028,33.041,46]hexa-
pentaconta-2,4,6,11(56),12,15,17,19,24(55),25,28,30,32,37(54),
38,41(46),42,44,50(53),51-icosaene-8,21,34,47-tetrone (17)
Macrocycle 17 was prepared from 16 according to GP 3A using a
reaction time of 2.5 h. The product was dissolved in AcOH–HCl
(85:15), and this soln was purified by column chromatography
(EtOAc).
References
(1) Wessjohann, L. A.; Ruijter, E.; Garcia-Rivera, D.; Brandt,
W. Mol. Diversity 2005, 9, 171.
(2) Tyndall, J. D. A.; Fairlie, D. P. Curr. Med. Chem. 2001, 8,
893.
(3) Nishino, N.; Wagner, R. N.; Lindsey, J. N. J. Org. Chem.
1996, 61, 7534.
(4) Hellier, P. C.; Bradshaw, J. S.; Young, J. J.; Zhang, X. X.;
Izatt, R. M. J. Org. Chem. 1996, 61, 7270.
(5) Rajakumar, P.; Murali, V. Tetrahedron 2000, 56, 7995.
(6) Kim, S. H.; Choi, S. H.; Kim, J.; Lee, S. J.; Quang, D. T.;
Kim, J. S. Org. Lett. 2010, 12, 560.
(7) Pirali, T.; Tron, G. C.; Zhu, J. Org. Lett. 2006, 8, 4145.
(8) Chandrasekhar, S.; Rao, C. L.; Nagesh, C.; Reddy, C. R.;
Sridhar, B. Tetrahedron Lett. 2007, 48, 5869.
(9) Yanai, H.; Taguchi, T. Tetrahedron Lett. 2005, 46, 8639.
(10) Ray, A.; Manoj, K.; Bhadbhade, M. M.; Mukhopadhyay, R.;
Bhattacharjya, A. Tetrahedron Lett. 2006, 47, 2775.
(11) Shao, C.; Wang, X.; Xu, J.; Zhao, J.; Zhang, Q.; Hu, Y.
J. Org. Chem. 2010, 75, 7002.
Yield: 1.3 g (65%); white solid; mp 277–280 °C.
IR (neat, ATR): 3139, 3068, 1738, 1717, 1601, 1503, 1457, 1287,
1264, 1239, 1142, 1127, 1094, 1047, 764, 757, 767 cm–1.
ESI-HRMS: m/z [M + H]+ calcd for C40H29N12O8: 805.22258;
found: 805.22247.
Macrocycle 17 was also prepared by reacting azide 16 (2.01 g, 2.5
mmol) in DMF (60 mL) with CuSO4 (0.16 g, 0.64 mmol) and ascor-
bic acid (0.3 g, 1.7 mmol) according to GP 3B. The reaction time
was 30 min.
Yield: 1.2 g (60%); mp 276–280 °C.
(12) Chen, H.; Zuo, S.; Tang, X.; Zhao, M.; Lu, Y.; Chen, L.; Liu,
J.; Liu, Y.; Liu, D.; Zhang, S.; Li, T.; Wang, X. Eur. J. Med.
Chem. 2011, 46, 4709.
(13) Majumdar, K. C.; Ray, K. Synthesis 2011, 3767.
(14) Hradilová, L.; Grepl, M.; Hlaváč, J.; Lyčka, A.; Hradil, P.
J. Heterocycl. Chem. 2012, in press.
Acknowledgment
This project was supported in part by the Ministry of Education,
Youth and Sport of the Czech Republic (grants MSM6198959216
and ME09057) and FM EEA/Norska (A/CZ0046/1/0022).
(15) Garanti, L.; Molteni, G.; Zecchi, G. Heterocycles 1994, 38,
291.
(16) More, S. S.; Shanmughapriya, D.; Lingam, Y.; Patel, N. B.
Synth. Commun. 2009, 39, 2058.
Synthesis 2012, 44, 1398–1404
© Georg Thieme Verlag Stuttgart · New York