Propargyl anthranilate derivatives and their application in the synthesis of rings containing 1,2,3-triazolo motifs

Article abstract of DOI:10.1002/jhet.1514

Propargyl anthranilate, a simple and less studied molecule with several reactive sites, is widely applicable in organic synthesis. An optimized synthesis of this compound and its derivatives and the preparation of azide derivatives are described. The optimized process of the known intramolecular cyclization is described, and the unknown intermolecular cyclizations of these azido derivatives and formation of a macrocycle are discussed.

Full text of DOI:10.1002/jhet.1514

Month 2013 Propargyl Anthranilate Derivatives and Their Application in the Synthesis
of Rings Containing 1,2,3-Triazolo Motifs
Ludmila Hradilová,1 Martin Grepl,1,2 Jan Hlaváč,1 Antonín Lyčka,3,4 and Pavel Hradil1,2
*
1Department of Organic Chemistry, Palacky University, Tr. 17. listopadu 12, CZ-771 46 Olomouc, Czech Republic
2Farmak a.s., Na Vlčinci 3, 77117 Olomouc, Czech Republic
3Research Institute for Organic Syntheses, Rybitví 296, CZ-533 54 Pardubice, Czech Republic
4University of Hradec Králové, Faculty of Science, Rokitanského 62, CZ-500 03 Hradec Králové 3, Czech Republic
*
E-mail: hradil@farmak.cz
Received May 15, 2011
DOI 10.1002/jhet.1514
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
Propargyl anthranilate, a simple and less studied molecule with several reactive sites, is widely applicable in
organic synthesis. An optimized synthesis of this compound and its derivatives and the preparation of azide
derivatives are described. The optimized process of the known intramolecular cyclization is described, and
the unknown intermolecular cyclizations of these azido derivatives and formation of a macrocycle are discussed.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
of considerable interest and are objects of patents of various
pharmaceutical companies. The pharmacological activities
of these compounds are variable and include antifungal
activity, anti-HIV activity, and calcium channel activity;
they also have applications as antidepressants or agents for
the treatment of lipoprotein disorders [4–7].
While testing, we found that 4H,6H-[1,2,3]triazolo[1,5-a]
[4,1]benzoxaze-pin-6-on has a moderate cytostatic activity.
This type of activity is unusual for similar types of com-
pounds but is common for the 3-hydroxy-4(1H)-quinolinone
derivatives. In most cases, the stability of the oxazepinone
derivatives is limited. Moreover, as we have shown in the
past, 3-hydroxy-4-(1H)-quinolinone derivatives were formed
instead of the oxazepinone derivative [9,10]. Because
the structure of 4H,6H-[1,2,3]triazolo[1,5-a][4,1]benzoxaze-
pin-6-on was documented only with elemental analysis and
1H-NMR [8], we decided to repeat the procedure described
above and to perform more advanced NMR analysis to verify
its structure.
Independent or annelated medium-sized heterocycles,
especially compounds with seven-membered rings, have
been receiving significant attention not only because of
the existence of their structural units in some natural
products [1] but also because this structural motif is com-
mon in pharmaceutically active compounds [2,3]. Of these,
possibly the most popular is a group of thousands of
compounds known as the “benzodiazepines.” The most
widely used benzodiazepine drug is diazepam. It is used as
an anxiolytic, a sedative, a muscle relaxant, and also as a
psychostimulant. It was observed that if the benzodiazepines
are annelated with triazole, their activity increases, and
hence, a lower dosage can be used. These structures are
represented by compounds such as triazolam or alprazolam.
Midazolam, a compound with an imidazole ring, is used
as an intravenous anesthetic [2]. Some members of this
group have also displayed antipsychotic activities [2,3].
Oxazepinone derivatives are much less frequent than
diazepinone derivatives, mainly because of their low
stability. Only the more stable dibenzooxazepinones are
Therefore, we studied the synthesis of this compound
and its derivatives, and our results are described here.
© 2013 HeteroCorporation

L. Hradilová, M. Grepl, J. Hlaváč, A. Lyčka, and P. Hradil
Vol 000
Scheme 1. Intermolecular dimerization of propargyl anthranilate.
RESULTS AND DISCUSSION
O
O
The cyclization of compound 2a into the oxazepinone
derivative 3a in boiling toluene was described recently
[8]. Besides the azido derivative 2a, we decided to also
prepare some derivatives (Fig. 1) and to compare their
reactivity during cyclization with the parent compound 2a.
Better results were obtained, compared with the described
procedure [8], for the synthesis of propargyl anthranilate 1a
if an excess of propargyl alcohol and only a catalytic amount
of sodium hydride were used. Derivatives 1b and 1c
were prepared in the same way by the reaction of isatoic
anhydride and 1,4-butynediol in toluene, with sodium
hydride as the catalyst. A mixture of these compounds
was formed, their ratio depending on the ratio of the
starting materials. Products 1a and 1b were separated
by column chromatography. The best yield for com-
pound 1b was 55%, and the best yield for the compound
1c was 48%. Derivative 1d was prepared by catalytic
oxidation of compound 1a using copper acetate as the
catalyst and hydrogen peroxide as an oxidation agent in
the yield of 87%. The process was more reproducible
than oxidation with atmospheric oxygen. Azido deriva-
tives 2 were prepared through the reaction of the diazo-
nium salts with sodium azide. The yield of the reaction
was high (73 to 95%), and the reaction proceeded well.
The products of this reaction are all in the form of a
solid, except for compound 2b. During the study of the
behavior of compound 2a, we found a deviation from
the described procedure, and the formation of other
compounds was observed. Later, we found that com-
pound 2a has limited stability and a new compound
4a was formed during storage (Scheme 1). The reaction
is quite slow, and only 50% of azide 2a decomposed
during 12 weeks at room temperature; thus, completion
of this reaction takes more than 1 year. The maximum
speed of dimerization for the preparation of compound
4a was observed at 40ꢀC. Under these conditions,
50% of azide 2a reacted after 44 h. A large number of
by-products were formed at higher temperatures, and the
reaction is not applicable for the preparation of com-
pound 4a under these conditions. Compound 2a was
stable at À20ꢀC for more than 1 year.
O
N
N
O
N
N3
N3
O
O
4a
66 %
2a
By heating the transformed product 4a in boiling
toluene, a new macrocyclic compound 5a was formed in
low yield (Scheme 2).
New procedures for the cyclization of azido derivatives
were developed, and older procedures were optimized.
The use of DMF for the cyclization of derivative 2a signif-
icantly reduced the reaction time, and the same method is
applicable for the preparation of the substituted derivative
3b (Scheme 3), where the final products are insoluble in
toluene. Compound 3b was prepared in 50% yield, and
compound 3c was prepared in the yield of 89%. This
method is also applicable in the preparation of derivative
5a from derivative 4a. Macrocycle 5a was prepared in
the yield of 32%. Because the formation of a triazole ring
from azide derivatives and a terminal alkyne group (known
as a “click reaction”) is performed in the presence of a
copper catalyst, the influence of copper catalysis was also
tested. Under these conditions, derivative 4a reacted
smoothly, and compound 5a was formed in mild condi-
tions in 50% yield. The cyclization of compound 2a with
copper catalysis was more complicated. The reaction was
very fast, and a solid precipitate separated from the boiling
solution in DMF within 20 min. The protonated molecule
of the expected compound 3a (m/z 202) was observed with
very low intensity in the MS spectra. Besides this, a low
intensity ion (m/z 403) corresponding to the protonated
molecule 5a was also observed. The NMR spectra also
revealed a rich mixture of compounds.
The behavior of compound 2a derivatives and their
stability were also studied. It was found that the stability
of compound 2b is also limited, but a rich mixture of
compounds is formed during its decomposition. The azido
O
6
8
9
5
4
7
O
10
1
R
2
X
3
O
X
O
6
8
9
1
2
1 X = NH2
2 X = N3
5
4
10
OCH2
O
7
a R = H; b R = CH2OH;
c R =
d R =
C
;
X
3
Figure 1. Some prepared derivatives besides the azido derivative 2a.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Propargyl Anthranilate Derivatives and Their Application in the Synthesis
of Rings Containing 1,2,3-Triazolo Motifs
Scheme 2. Formation of macrocycle 5a.
O
O
10
3
8
6
3
13
15
12
10
1
N
N
9
2
O
7
DMF
4
5
4
O
1
9
14
N
N
N
6
11
16
17
8
5
N
5
A 32 %
B 50 %
2
6
N
N3
7
7
9
4
O
2
3
1
O
N
8
O
N
18
4a
5a
O
10
19
20
Scheme 3. Optimized method for the formation of benzoxazepinones 3 from azido derivatives 2.
O
O
8
6
6
9
O
8
7
7
5
4
DMF
reflux
5
4
10
O
1
2
1
R
9
2
N3
N
3
3
R
N
10
2a,b,c
3a 92 %
3b 50 %
3c 89 %
N
R = a) H
b) CH2OH,
11
O
O
3c)
2c)
CH2OC
N3
14
CH2OC
N3
2
13
1
12
7
8
11
18
6
15
3
5
16
17
4
derivatives 2c and 2d are stable, and they were unchanged
during storage at room temperature for more than 1 year.
Various routes for thermal cyclization were tested for
these compounds.
CONCLUSION
The structure of 4H,6H-[1,2,3]triazolo[1,5-a][4,1]
benzoxazepin-6-on (3a), which was previously described
[8], was verified with advanced NMR techniques. A
modified procedure for the preparation of compounds 3a–3c
was described. The limited stability and unexpected
intermolecular cyclization of propargyl 2-azidobenzoate 2a
was also found, and the formation of the new macrocycle
5a was described.
Derivative 2c reacted similarly as before, and deriva-
tive 3c was formed. Conversely, during thermal cycliza-
tion of compound 2d, the reaction was observed after
4 h, and a complex mixture was formed. Reaction with
copper (as catalyst) was not effective for derivatives
other than 1a. Instead of cyclization, a reduction was
observed, and the amount of catalyst (ascorbic acid
and copper sulfate) had to be increased to complete
the reaction. The mixture of aminoderivatives 1b, 1c,
or 1d was formed in this case.
Cytostatic activities of the newly prepared compounds
were tested. Such an activity was not found for most of
the compounds. Weak activity against the leukemia cell
line K-562 was found only for compound 3c, with an
IC50 of 100 mM.
EXPERIMENTAL
All reagents were of commercial quality (Fluka, Aldrich,
Prague, Czech Republic) and were used as received. Reactions
were monitored by thin layer chromatography on plastic plates
coated with silica gel (Polygram Sil G/UV254, Macherey-Nagel,
Düren; Germany). Melting points were measured in a Köfler
apparatus and are uncorrected. Elemental analysis was performed
on an EA 1108 (Fisons Instruments, Waltham, USA).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

L. Hradilová, M. Grepl, J. Hlaváč, A. Lyčka, and P. Hradil
Vol 000
NMR spectra of compound 1 was obtained on a Bruker
AVANCE 300 (Rheinstetten, Germany) at 300.13 (1H) and
75.47 MHz (13C), whereas the NMR spectra of all other com-
pounds were recorded on a Bruker AVANCE II 400 at 400.13
(1H) and 100.62 MHz (13C). The samples were dissolved in
another 30 min. The excess of propargyl alcohol was removed by
distillation in vacuo.
The residue was cooled to 30ꢀC and acidified with acetic acid
(one to two drops). The reaction mixture was then diluted with
water (200 mL), cooled to 0–5ꢀC, and filtered. After letting the
reaction mixture stand for 15 min, the solid was washed with water
and dried in vacuo. The yield was 53.3 g (99.3%), mp 35–37ꢀC.
For analysis, the hydrochloride of 1a was prepared by precipitation
from a diethyl ether solution by the addition of an ethanolic solution
of HCl, mp 165–168ꢀC (lit [11] mp 176–177ꢀC; lit [8] mp 169ꢀC)
1
DMSO-d6. H and 13C chemical shifts were in reference to the
central signal of the solvent [d = 2.55 (1Η) and d = 39.6
(13C)]. All 2D experiments [gradient-selected (gs)-COSY, gs-
HMQC, gs-HMBC] were performed using the manufacturer’s
software (TOPSPIN 2.1). Proton spectra were assigned using
gs-COSY. Protonated carbons were assigned by gs-1H–13C
HMQC, and quaternary carbons were assigned by gs-1H–13C
HMBC. The numbering of compounds for NMR purposes is
given in Figure 1 and Schemes 2 and 3. NMR data for mole-
cules 1–5 are summarized in Table 1.
MS m/z (relative intensity) 232 (13) [M + t-butyl]+, 218 (4)
[M + C3H7]+, 176 (40) [M + H]+, 120 (100) [H2NC6H4CO]+, 92
(10), 79 (5). NMR data are given in Table 1.
Preparation of 4-hydroxybut-2-yn-1-yl anthranilate (1b)
and but-2-yn-1,4-diyl dianthranilate (1c)
MS characterization was carried out using the DEP–CI–MS
(direct exposure probe–chemical ionization–mass spectrometry)
technique with a quadrupole ion trap mass analyzer and isobutane
as a CI reagent gas.
Preparation of propargyl anthranilate (1a). Sodium hydride
(200 mg) was added to a suspension of isatoic anhydride (50 g,
0.307mol) in propargyl alcohol (100g, 1.78mol), and the
mixture was heated to reflux. The initial solid disappeared, and a
clear solution was formed in 1.5 to 2 h. Afterward, the reaction
was checked by TLC (AcOEt: n-hexane 7:3). If residual isatoic
anhydride was present, the reaction was heated to reflux for
Procedure A. To a suspension of isatoic anhydride (10 g, 61.3 mmol)
in toluene (100 mL), butynediol (5.3 g, 61.6 mmol) and sodium
hydride (60 mg) were added. The reaction mixture was heated in a
water bath at 60ꢀC. The suspended solid dissolved in 20 min. After
consumption of the starting material (confirmed by TLC) after
approximately 1 h, an oily layer was separated. The reaction
mixture was concentrated using a vacuum evaporator. The resulting
residue was stirred with a saturated solution of sodium carbonate
(100 mL) and extracted with ethyl acetate (3 Â 70 mL). The organic
extract was initially dried with sodium sulfate and finally on a
vacuum evaporator. The final products were separated from the oily
Table 1
1H and 13C NMR data (d, ppm) of compounds 2–5 in DMSO-d6.
Position
Compound
1
2
3
4
5
6
7
8
9
10
11
1a
1b
dH
dC
–
–
6.76
7.25
6.52
7.67
–
4.86
–
79.3
–
79.3
–
81.8
–
76.0
–
78.4
–
78.4
–
81.7
–
75.6
–
133.8
–
131.1
–
133.0
–
3.55
78.0
–
87.0
–
108.3
–
108.4
–
108.3
–
152.1
–
152.0
–
152.1
–
152.2
–
139.4
–
139.4
–
139.6
–
139.8
–
132.7
–
132.8
–
132.7
–
139.2
–
117.1
6.76
117.1
6.76
117.1
6.76
117.1
7.44
120.9
7.44
120.9
7.41
121.2
7.42
121.2
8.11
122.4
8.10
122.3
8.12
122.4
7.48
120.9
5.22
58.1
134.9
7.25
134.9
7.25
134.9
7.25
135.0
7.70
134.1
7.70
134.1
7.65
134.4
7.65
134.6
7.76
129.5
7.76
129.4
7.79
129.7
7.70
133.8
115.3
6.52
115.3
6.52
115.3
6.51
115.3
7.33
125.1
7.33
125.1
7.28
125.4
7.28
125.4
7.99
125.0
7.97
135.0
8.00
135.0
7.34
125.0
8.44
127.1
131.0
7.67
131.0
7.67
131.0
7.66
131.0
7.83
131.4
7.93
131.4
7.77
131.6
7.78
131.8
8.11
133.9
8.10
133.9
8.12
134.0
7.87
131.3
166.9
–
167.0
–
166.9
–
166.8
–
164.1
–
164.1
–
164.3
–
164.2
–
166.8
–
167.0
–
166.7
–
164.4
52.0
4.91
52.2
4.96
52.1
5.02
52.4
5.01
53.1
5.01
53.1
5.01
53.1
5.07
53.4
5.54
55.8
5.56
56.6
5.66
56.3
5.51
58.1
7.90
133.7
dH
dH
dH
dH
dH
dH
dH
dH
dH
dH
dH
dH
4.10
49.4
1c
dC
dC
dC
dC
dC
dC
dC
dC
dC
dC
dC
dC
1d
2a
2b
2c
–
69.7
3.31
121.8
–
–
121.8
–
121.8
–
122.0
–
121.6
–
122.9
–
122.7
–
122.7
–
122.2
–
4.19
49.2
87.3
–
2d
3a
3b
3ca
4ab
5a
–
70.0
8.15
133.0
–
145.7
–
140.0
8.75
126.5
8.15
131.5
–
–
7.78
54.4
5.64
57.1
–
135.5
–
–
142.0
7.84
130.6
–
–
7.65
127.3
127.0
165.0
141.4
135.5
a–/164.5 (12), –/139.2 (13), –/121.9 (14), 7.48/120.9 (15), 7.70/134.0 (16), 7.34/125.1 (17), 7.84/131.3 (18).
b7.76/126.8 (12), 7.90/133.6 (13), 7.79/130.4 (14), 8.03/130.8 (15), –/126.4 (16), –/164.2 (17), 4.78/53.0 (18), –/78.3 (19), 3.61/77.6 (20).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Propargyl Anthranilate Derivatives and Their Application in the Synthesis
of Rings Containing 1,2,3-Triazolo Motifs
residue by column chromatography on silica gel using a 1:1
mixture of n-hexane : AcOEt as the eluent.
The yield of compound 1b was 6.9 g (55%), mp 65–69ꢀC.
Anthranilates 1 (3 mmol) were dissolved in ethanol or acetone
(5 mL), concentrated hydrochloric acid (0.8 mL) was added
dropwise, and a solution of sodium nitrite (0.207 g, 3 mmol) in
water (0.5 mL) was added at À10 to 0ꢀC. The reaction mixture
was stirred for 15 min at this temperature, and then a solution of
sodium azide (0.195 g, 3 mmol) in water (1 mL) was added in
drops. During the reaction, the solids were precipitated. After
consumption of the starting material (monitored by TLC;
approximately 1 h), water was added (15 mL), and the precipi-
tated solid was filtered off, washed with water or extracted
with AcOEt (3 Â 25 mL) in the case of oily azides. The isolated
azides were used in the next reaction step without further
purification.
Propargyl 2-azidobenzoate (2a). The preparation of this com-
pound was performed in ethanol with 1a (10g, 57.08mmol).
The yield of product 2a was 10.7 g (93%), mp 63–66ꢀC (lit [8]
mp 65ꢀC).
Calculated for C10H7N3O2 (201.18): 59.70% C; 3.51% H;
20.89% N; found: 59.48% C; 3.39% H; 21.05% N. MS m/z
(relative intensity) 230 (20) [M À N2 + t-butyl]+, 216 (4) [M À N2 +
C3H7]+, 202 (3) [M+ H]+, 174 (100) [M + H À N2]+, 156 (45), 146
(44), 144 (20), 132 (16), 130 (22), 128 (21), 120 (53)
[H2NC6H4CO]+, 103 (23), 92 (10), 89 (10). NMR data are given
in Table 1.
2-Azido-benzoic acid 4-hydroxy-but-2-ynyl ester (2b). This
procedure was performed with 1b (0.5 g, 2.44 mmol) in
ethanol. The yield of the yellow–red oily product 2b was
0.4 g (71%).
Calculated for C11H9N3O3 (231.207): 57.14% C; 3.92% H;
18.17% N; found: 57.48% C; 4.13% H; 17.91% N. MS m/z
(relative intensity) 260 (18) [M À N2 + t-butyl]+, 247 (4) [M À N2 +
C3H7]+, 232 (2) [M+ H]+, 204 (45) [M + H À N2]+, 186 (35), 177
(33), 176 (32), 158 (100), 146 (10), 130 (77), 120 (61)
[H2NC6H4CO]+, 103 (18), 92 (15), 65 (5). NMR data are given
in Table 1.
Calculated for C11H11NO3 (205.21): 64.38% C; 5.40% H;
6.83% N; found: 64.05% C; 5.29% H; 6.98% N. MS m/z (relative
intensity) 262 (8) [M+ t-butyl]+, 248 (4) [M +C3H7]+, 206 (60)
[M + H]+, 188 (4) [M + H À H2O]+, 120 (100) [H2NC6H4CO]+,
1
92 (10). H NMR (DMSO-d6, 300MHz) d 7.69 (1H, dd, J = 7.9;
1.3 Hz); 7.27 (1H, dt, J= 7.9; 1.5 Hz); 6.78 (1H, d, J=8.4Hz);
6.66 (2H, s); 6.54 (1H, t, J= 7.7 Hz); 5.23 (1H, t, J=6.0 Hz); 4.93
(2H, t, J= 1.6 Hz); 4.12 (2H, td, J= 6.1; 1.6 Hz); 13C NMR
(DMSO-d6, 75MHz) d 166.4; 151.6; 134.4; 130.5; 116.6; 114.8;
107.8; 81.3; 51.6. NMR data are given in Table 1.
The yield of compound 1c was 3.0 g (15%), mp 100–102ꢀC.
Calculated for C18H16N2O4 (324.331): 66.66% C; 4.97% H;
8.64% N; found: 66.35% C; 4.80% H; 8.77% N. MS m/z (relative
intensity) 381 (11) [M + t-butyl]+, 367 (5) [M + C3H7]+, 325 (90)
[M + H]+, 190 (10), 188 (25) [M + H À anthranilate]+, 158 (5),
138 (17) [H2NC6H4COOH2]+, 120 (100) [H2NC6H4CO]+, 92
(10). 1H NMR (DMSO-d6, 300 MHz) d 7.69 (2H, dd, J = 8.0;
1.3 Hz); 7.27 (2H, dt, J = 7.9; 1.5 Hz); 6.78 (2H, d, J = 8.3 Hz);
6.66 (4H, s); 6.54 (2H, dt, J = 7.5; 0.9 Hz); 4.98 (4H, s); 13C
NMR (DMSO-d6, 75 MHz) d 166.4; 151.6; 134.4; 130.5; 116.6;
114.8; 107.8; 81.3; 51.6. NMR data are given in Table 1.
Procedure B. The same procedure as Procedure A was applied
with the following modifications: isatoic anhydride (10 g,
61.3mmol), butynediol (2.6 g, 30mmol). The yield of compound
1b was 1.4 g (12%), and the yield of compound 1c was 8.6 g (48%).
Hexa-2,4-diyn-1,6-diyl dianthranilate (1d). Propargyl anthrani-
late 1a (3 g; 17.12 mmol) was dissolved in DMF (30 mL). Copper
acetate (0.5 g, 2.75 mmol) and ferrous chloride (0.1 g; 0.79 mmol)
were added, and the reaction mixture was heated to 80ꢀC. Then,
hydrogen peroxide (35%; 2 mL, 20.5 mmol) was slowly added.
The reaction time was approximately 2–2.5 h. If the reaction still
contained starting material 1a, a new portion of hydrogen peroxide
(1 mL) was added. After the starting material was completely
converted, the reaction was filtered with charcoal (0.2 g), the filter
cake was washed with hot DMF (5 mL), the filtrate was
concentrated on a vacuum evaporator, and the residue was diluted
with water (50 mL). Afterward, AcOEt (100 mL) and charcoal
(0.5g) were added, and the reaction mixture was filtered. The
organic layer was separated, and the water layer was extracted
twice with AcOEt (50 mL). Then, the organic layer was separated,
dried over sodium sulfate, and filtered through a layer of silica gel.
The AcOEt was then evaporated, and the solid was dissolved in
acetone (3 mL). Then, ethanol (30 mL) was added, and the acetone
was evaporated in vacuo. The precipitated solid was filtered, and
the yield of product 1d was 2.6 g (87%), mp 139-142ꢀC.
2-Azido-benzoic acid 4-(2-azido-phenoxy)-but-2-ynyl ester
(2c). This procedure was performed with 1c (1 g; 3.08 mmol) in
acetone. The yield of product 2c was 1.1 g (95%) mp 59–62ꢀC.
Calculated for C18H12N6O4 (376.326): 57.45% C; 3.21% H;
22.33% N; found: 57.30% C; 3.06% H; 22.51% N. MS m/z
(relative intensity) 405 (3) [MÀ N2 + t-butyl]+, 377 (2) [M + H]+,
349 (9) [M+ H À N2]+, 321 (100) [M + H À N2 À N2]+, 303 (10),
277 (7), 275 (8), 261 (7), 259 (7), 253 (10), 251 (21), 247
(12), 237 (9), 233 (8), 214 (8), 209 (11), 188 (8), 186 (11), 170
(7), 158 (7), 138 (8), 130 (7), 120 (39) [H2NC6H4CO]+, 92 (13),
65 (5). NMR data are given in Table 1.
Hexa-2,4-diyn-1,6-diyl bis(2-azidobenzoate) (2d). This pro-
cedure was performed with 1d (0.5 g, 1.44 mmol) in acetone. The
yield of product 2d was 0.54 g (95%), mp 79–81ꢀC.
Calculated for C20H12N6O4 (400.35): 60.00% C; 3.02% H;
20.99% N; found: 59.86% C; 2.95% H; 21.13% N. MS m/z
(relative intensity) 429 (4) [M À N2 + t-butyl]+, 401 (<2) [M + H]+,
373 (4) [M + H À N2]+, 345 (15) [M+ H À N2 À N2]+, 327 (10),
315 (7), 301 (14), 299 (15), 273 (8), 271 (10), 256 (7), 210
(10), 194 (9), 148 (7), 138 (38) [H2NC6H4COOH2]+, 120 (100)
[H2NC6H4CO]+, 92 (35), 79 (10), 65 (8). NMR data are given
in Table 1.
General procedure for the cyclization of azido derivatives
2 or 4a. Azides 2 or 4a (2.5 mmol) were dissolved in DMF (10 mL).
The reaction mixture was refluxed for 30 min and then checked
for completion of reaction by TLC. If the starting material was
not present (TLC control), the reaction mixture was cooled and
Calculated for C20H16N2O4 (348.35): 68.96% C; 4.63% H;
8.04% N; found: 68.75% C; 4.51% H; 8.14% N. MS m/z
(relative intensity) 405 (5) [M + t-butyl]+, 391 (3) [M+ C3H7]+,
349 (50) [M + H]+, 214 (8), 212 (18) [M + H À anthranilate]+,
196 (9), 194 (7), 168 (5), 138 (35) [H2NC6H4COOH2]+, 120
(100) [H2NC6H4CO]+, 92 (15), 79 (5). NMR data are given
in Table 1.
General procedure for the preparation of azido derivatives
2a–2d.
Caution! Although no problems were observed during
the handling of the azido derivatives, these compounds
may be explosive and are potentially dangerous!
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

L. Hradilová, M. Grepl, J. Hlaváč, A. Lyčka, and P. Hradil
Vol 000
poured into water. The precipitated solid was filtered off, dried in
vacuo, and recrystallized from acetone.
Calculated for C20H14N6O4 (402.36): 59.70% C; 3.51% H;
20.89% N; found: 59.78% C; 3.63% H; 21.01% N. MS m/z
(relative intensity) 459 (3) [M + t-butyl]+, 445 (3) [M + C3H7]+,
443 (3) [M + C3H5]+, 441 (5) [M + C3H3]+, 403 (100) [M + H]+,
375 (15) [M + H À CO]+, 301 (3), 204 (3), 174 (10), 156
(10), 146 (5), 130 (4), 120 (4) [H2NC6H4CO]+, 79 (4), 74 (6).
NMR data are given in Table 1.
Preparation of 4H,6H-[1,2,3]triazolo[1,5-a][4,1]benzoxazepin-
6-on (3a). This was performed according to the general procedure
with azido derivative 2a (10g, 49.71mmol) in DMF (25mL),
with a reaction time of 45–60min. The yield of product 3a was
9.2 g (92%), mp 210–212ꢀC (lit [8] mp 194ꢀC).
Procedure B. Azido derivative 4a (1 g, 2.5 mmol) was dissolved
in DMF (30 mL). A solution of copper sulfate heptahydrate (0.1 g,
0.40 mmol) in water (3 mL) and a solution of ascorbic acid (0.15 g,
0.85 mmol) in water (3 mL) were added. The reaction mixture was
stirred at room temperature. The starting material was not observed
by TLC after 15 min, after which a solid compound was
precipitated and the reaction mixture was stirred for 3 h. Then, the
reaction mixture was poured into a mixture of water and ice
(200 g). The precipitate was filtered off and washed with water.
The solid compound was then dried and dissolved in hydrochloric
acid (10 mL). This solution was dispersed onto silica gel, and the
column was washed with a mixture of toluene (500 mL), ethyl
acetate (500 mL), and formic acid (20 mL). In this first rinse, the
impurities were removed. Then, the column was washed with a
mixture of ethyl acetate (500 mL) and formic acid (20 mL). This
part of the eluent was evaporated in vacuo; a solid white product
was isolated, washed with a solution of ammonium bicarbonate,
and recrystallized from DMF. The yield of product 5a was 0.5 g
(50%), mp 328–330ꢀC.
Calculated for C10H7N3O2 (201.181): 59.70% C; 3.51% H;
20.89% N; found: 59.55% C; 3.42% H; 20.96% N. MS m/z
(relative intensity) 258 (15) [M +t-butyl]+, 244 (4) [M + C3H7]+,
202 (100) [M + H]+, 174 (4) [M + H À CO]+, 146 (7) [M + H À CO
N2]+, 118 (4). NMR data are given in Table 1.
3-(Hydroxymethyl)-4H,6H-[1,2,3]triazolo[1,5-a][4,1]benzo-
xazepin-6-one (3b). This was performed according to the general
procedure with 2b (0.5 g, 2.16 mmol), with a reaction time
of 20 min. The yield of product 3b was 0.25 g (50%), mp
191–195ꢀC.
Calculated for C11H9N3O3 (231.21): 57.14% C; 3.92% H;
18.17% N; found: 57.27% C; 4.01% H; 18.05% N. MS m/z (rel-
ative intensity) 288 (6) [M + t-butyl]+, 274 (4) [M + C3H7]+, 232
(100) [M + H]+, 204 (6) [M + H À CO]+, 188 (5), 186 (7) [M + H
CO À H2O]+, 158 (20) [M + H À CO À H2O À N2]+, 132 (4),
120 (6) [H2NC6H4CO]+, 104 (4), 81 (3), 79 (7), 67 (4). NMR data
are given in Table 1
4H,6H-[1,2,3]Triazolo[1,5-a][4,1]benzoxazepin-6-one-3-methyl
2-azidobenzoate (3c). This was performed according to the general
procedure with 2c (1 g, 2.66 mmol), with a reaction time of 45 min.
The yield of product 3c was 0.89 g (89%), mp 177–180.5ꢀC.
Calculated for C18H12N6O4 (376.33): 57.45% C; 3.21% H;
22.33% N; found: 57.31% C; 3.09% H; 22.49% N. MS m/z (rela-
tive intensity) 433 (9) [M + t-butyl]+, 419 (3) [M + C3H7]+, 415 (5)
[M + C3H3]+, 377 (60) [M + H]+, 349 (100) [M + H À N2]+,
321 (3) [M + H À N2 À CO]+, 320 (5), 275 (5), 263 (15), 247
(5), 232 (7), 230 (14), 216 (4), 204 (4), 186 (50), 174 (4), 158
(15), 146 (5), 138 (5), 132 (5), 130 (12), 120 (15) [H2NC6H4CO]+,
94 (4), 92 (10), 79 (3). NMR data are given in Table 1.
Preparation of prop-2-yn-1-yl 2-(4-{[(2-azidophenyl)carbonyloxy]
methyl}-1H-1,2,3-triazol-1-yl)benzoate (4a). The solid compound
2a was allowed to stand at laboratory temperature for 1 year.
Compound 4a was formed. The dimer was purified by column
chromatography on silica gel. The yield of product 4a was 0.66 g
(66%), mp 131–133ꢀC.
Acknowledgment. This project was supported in part by the Min-
istry of Education, Youth and Sports of the Czech Republic (grants
MSM6198959216 and ME09057).
REFERENCES AND NOTES
[1] Fox, C. H.; Klein, E.; Huneck, S. Phytochemistry 1970, 9,
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Calculated for C20H14N6O4 (402.36): 59.70% C; 3.51% H;
20.89% N; found: 59.58% C; 3.46% H; 21.08% N. MS m/z
(relative intensity) 459 (3) [M + t-butyl]+, 403 (10) [M + H]+,
375 (4) [M + H À N2]+, 293 (3), 258 (7), 242 (4), 239 (4), 230
(4), 202 (50), 174 (100), 156 (8), 148 (6), 146 (18), 138 (6),
130 (10), 120 (25) [H2NC6H4CO]+, 92 (5), 79 (3). NMR data
are given in Table 1.
Preparation of 9,22-Dioxa-1,12,13,14,25,26-hexaazapentacyclo
[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(5a)
Procedure A. This was performed according to the general
procedure with 4a (1 g, 2.5 mmol) in DMF (30 mL), with a
reaction time of 1.5 h. The wet product was washed in warm
acetone (200 mL), and the yield of product 5a was 0.32 g
(32%), mp 328–331ꢀC.
[5] Du Pont Pharmaceuticals Company (by A. J. Cocuzza, and
J. D. Rodgers) US Patent, 6, 140 320, 2002; Chem Abstr 1999, 130,
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[6] Nishimoto, T.; Ishikawa, E.; Anayama, H.; Hamajyo, H.;
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223, 39.
[7] Ajinomoto Co (by K. Sakata, T. Tsuji, N. Sasaki, and
K. Takahashi) US Patent 6, 562 808 2000; Chem Abstr 1999, 130,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet