Synthesis of macrocyclic systems from 4,4'-diamino-3,3'-bi-1,2,5-oxadiazole and 3(4)-amino-4(3)-(4-amino-1,2,5-oxadiazol-3-yl)-1,2,5-oxadiazole 2-oxides

Article abstract of DOI:10.1007/s11172-008-0101-0

Oxidative cyclocondensation of 4,4'-diamino-3,3'-bi-1,2,5-oxadiazole and isomeric 3(4)-amino-4(3)-(4-amino-1,2,5-oxadiazol-3-yl)-1,2,5-oxadiazole 2-oxides under the action of dibro-moisocyanurate gave 12- and 18-membered macrocyclic systems containing two or three bifurazanyl or furazanylfuroxanyl moieties linked by azo bridges. The latter were oxidized into azoxy groups with Caro's acid in 20% oleum.

Full text of DOI:10.1007/s11172-008-0101-0

Russian Chemical Bulletin, International Edition, Vol. 57, No. 3, pp. 644—651, March, 2008
644
Synthesis of macrocyclic systems from
4,4´ꢀdiaminoꢀ3,3´ꢀbiꢀ1,2,5ꢀoxadiazole and 3(4)ꢀaminoꢀ
4(3)ꢀ(4ꢀaminoꢀ1,2,5ꢀoxadiazolꢀ3ꢀyl)ꢀ1,2,5ꢀoxadiazole 2ꢀoxides

M. A. Epishina, A. S. Kulikov, and N. N. Makhova
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: mnn@ioc.ac.ru
Oxidative cyclocondensation of 4,4´ꢀdiaminoꢀ3,3´ꢀbiꢀ1,2,5ꢀoxadiazole and isomeric 3(4)ꢀamiꢀ
noꢀ4(3)ꢀ(4ꢀaminoꢀ1,2,5ꢀoxadiazolꢀ3ꢀyl)ꢀ1,2,5ꢀoxadiazole 2ꢀoxides under the action of dibroꢀ
moisocyanurate gave 12ꢀ and 18ꢀmembered macrocyclic systems containing two or three bifurazanyl
or furazanylfuroxanyl moieties linked by azo bridges. The latter were oxidized into azoxy groups with
Caro´s acid in 20% oleum.
Key words: 4,4´ꢀdiaminoꢀ3,3´ꢀbiꢀ1,2,5ꢀoxadiazole, 3(4)ꢀaminoꢀ4(3)ꢀ(4ꢀaminoꢀ1,2,5ꢀoxadiaꢀ
zolꢀ3ꢀyl)ꢀ1,2,5ꢀoxadiazole 2ꢀoxides, dibromoisocyanurate, azoꢀ and azoxybifurazanyl macrocyꢀ
cles, azoꢀ and azoxyfurazanylfuroxanyl macrocycles, oxidative cyclocondensation, oxidation,
azo derivatives, azoxy derivatives.
Conjugated macrocyclic systems containing nitrogen
heterocycles are well known. For instance, natural macꢀ
rocyclic compounds such as porphyrins and corrins are
found in hemoglobin, vitamin B12, and many enzymes
and coenzymes. Macrocyclic phthalocyanines are widely
used in the synthesis of organic dyes and dye intermediꢀ
ates. That is why the progress in the chemistry of such
structures containing various heterocycles in the macroꢀ
cyclic system is of considerable interest for organic, coꢀ
ordination, analytical, and biological chemists.
Our laboratory has been investigating for many years
1,2,5ꢀoxadiazoles (furazans) and their 2ꢀoxides (furoxꢀ
ans).1—3 Earlier, we have synthesized macrocyclic sysꢀ
tems containing alternating azoꢀ or azoxyfurazanyl
fragments4—8 and furazanꢀcontaining aza crown comꢀ
pounds.9,10 These compounds have been mostly syntheꢀ
sized via various versions of oxidative macrocyclization
of diaminofurazan or amino(hydroxyalkyl)furazans.
Analogous macrocyclic systems containing the furoxan
(furazan 2ꢀoxide) ring have not been documented.
The goal of the present work was to study the possibility
of oxidative macrocyclization of diamino derivatives
containing ensembles of two 1,2,5ꢀoxadiazole rings:
4,4´ꢀdiaminoꢀ3,3´ꢀbiꢀ1,2,5ꢀoxadiazole (1) and isomeric
3(4)ꢀaminoꢀ4(3)ꢀ(4ꢀaminoꢀ1,2,5ꢀoxadiazolꢀ3ꢀyl)ꢀ1,2,5ꢀ
oxadiazole 2ꢀoxides (2 and 3).
developed a method for their synthesis from accessible
4ꢀaminofurazanꢀ3ꢀcarbohydroximamide,13 which was
converted with NaNO2 in HCl into the corresponding
acid chloride 4 according to a known procedure14 and
further, with KCN, into nitrile 5. Treatment of the latter
with hydroxylamine hydrochloride in the presence of
NaHCO3 in boiling aqueous methanol gave a mixture
of synꢀ and antiꢀisomers of 1ꢀaminoꢀ2ꢀ(4ꢀaminofurazanꢀ
3ꢀyl)glyoxime 6. Starting from compound 6, we obtained
(1) 4,4´ꢀdiaminoꢀ3,3´ꢀbiꢀ1,2,5ꢀoxadiazole (1) by deꢀ
hydration of the vicinal oxime groups in boiling aqueꢀ
ous alkali and (2) 3ꢀaminoꢀ4ꢀ(4ꢀaminoꢀ1,2,5ꢀoxadiazꢀ
olꢀ3ꢀyl)ꢀ1,2,5ꢀoxadiazole 2ꢀoxide (2) by oxidative cyꢀ
clization of the glyoxime fragment into a furoxan ring
with bromine or K3Fe(CN)6. Diamine 2 was almost
completely isomerized into diamine 3 in boiling dioxane
(Scheme 1).
4,4´ꢀDiaminoꢀ3,3´ꢀbiꢀ1,2,5ꢀoxadiazole (1) has been
obtained earlier,11,12 although its yield did not exceed
18—20%. Isomeric diaminofurazanylfuroxans 2 and 3
have not been documented. For this reason, we initially
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 631—638, March, 2008.
1066ꢀ5285/08/5703ꢀ644 © 2008 Springer Science+Business Media, Inc.

Macrocycles from bi(1,2,5ꢀoxadiazoles)
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 3, March, 2008
645
Scheme 1
show signals for the C atoms in the same region as
for compounds 7 and 8.
Scheme 2
Reagents and conditions: DBI—MeCN, 20 °C.
According to Xꢀray diffraction data,16 the bifurazanyl
fragments in compound 7 are trans with respect to the azo
groups. By analogy, as well as from Xꢀray diffraction data
for the known azoꢀ and azoxyfurazanyl macrocycles,4—10
one can assume that the bifurazanyl and furazanylfuroxaꢀ
nyl fragments in compound 8 and the other macrocyclic
compounds obtained will also be trans with respect to
the azoꢀ and azoxy groups. The structural formulas shown
in the schemes are conventional because they do not
reflect the real spatial structures of these macrocycles.
Macrocyclic compounds could be obtained from diꢀ
amines 2 and 3 (1) via macrocyclization of presyntheꢀ
sized linear intermediates containing the azoꢀbridged
fragments of these diamines or (2) via their direct macroꢀ
cyclization (Scheme 3). We tried to synthesize linear
structures by oxidizing diamines 2 and 3 with KMnO4.
However, the target linear azo derivative was obtained
only from diamine 2; the reaction regiospecifically gave
compound 9 in 71% yield out of other possible azofuraꢀ
zanylfuroxan isomers (i.e., only the amino groups in poꢀ
sition 3 of the furoxan ring were involved in the reaction).
Such a selectivity of the oxidation is probably due to
the increased electron density at the above amino groups
because of the electronꢀreleasing effect of the Nꢀoxide
fragment in structure 2 compared to the electron density
at the amino groups in the furazan ring and in position 4
of the furoxan ring. The Nꢀoxide fragments in compound
9 were located from the signal at δ 128.64 in its 13C NMR
spectrum. This region (δ 123.2—125.7) is characteristic
Prior to the synthesis of macrocyclic compounds, we
studied the oxidative macrocyclization of 4,4´ꢀdiaminoꢀ
3,3´ꢀbiꢀ1,2,5ꢀoxadiazole 1 with dibromoisocyanurate
(DBI) as an oxidant. The reaction was carried out in
acetonitrile at room temperature. The complete converꢀ
sion of the starting diamine 1 was reached in 48 h (monꢀ
itoring by TLC). The reaction afforded a mixture of two
macrocyclic compounds 7 and 8 containing two and three
azobifurazanyl fragments, respectively (Scheme 2).
The products were separated by preparative column chroꢀ
matography on silica gel in close yields (~30%, each).
(Preliminary reports on the synthesis of compounds 7
and 8 and Xꢀray diffraction data for compound 7 have
been published earlier.15,16) Apparently, this reaction
also gives larger macrocycles, which is evident from 13C
NMR spectra of the third fraction separated by chromaꢀ
tography from the other reaction products: the spectra

646
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 3, March, 2008
Epishina et al.
of signals for the C atom in position 3 of the furoxan ring
bound to the azo group.17,18 The mass spectrum of comꢀ
pound 9 was not recorded because of its insufficient volꢀ
atility. Using acetic anhydride, we converted compound
9 into N,N´ꢀdiacetyl derivative 10 and recorded its mass
spectrum. Although the spectrum contained no molecuꢀ
lar ion peak (M+ = 448), the fragmentation ions correꢀ
sponded to the furazanylfuroxanyl fragment (238) conꢀ
taining the N=N and NHCOMe groups and to the same
fragment without the N=N group (210). These data proꢀ
vided additional evidence for the proposed structure.
For the macrocyclization of diamines 2 and 9, we
used the same oxidant (DBI) as with 4,4´ꢀdiaminoꢀ3,3´ꢀ
biꢀ1,2,5ꢀoxadiazole (1). In both cases, the roomꢀtemperꢀ
ature reaction in acetonitrile gave macrocyclic compound
11 as the sole product. The identical products obtained in
the macrocyclization of diamines 9 and 2 additionally
confirmed the structure of macrocycle 11 (Scheme 3).
product are insufficient for unambiguous assignment of
its structure to one of two possible isomers 12 and 13
(headꢀtoꢀhead or headꢀtoꢀtail cyclization of two starting
molecules) (Scheme 4).
Scheme 4
or
Scheme 3
Thus, the direct oxidation of the starting diamines 2
and 3 afforded both the target macrocyclic compounds 11
and 12 (or 13), although in low yields. Apparently, their
low yields in this macrocyclization reaction are due to
the formation of linear oligomers and larger macrocycles
that were detected at the start line in the thinꢀlayer chroꢀ
matography of the final mixture. The yields of macrocyꢀ
clic compounds 11 and 12 (or 13) were not increased
even by high dilution of the reaction mixture to a gram of
the starting amine per 100 mL of the solvent.
To oxidize the azo groups of the macrocyclic systems
obtained into azoxy groups, we studied various oxidative
mixtures based on hydrogen peroxide, sulfuric acid or
oleum, and sodium tungstate. We found that the oxidaꢀ
tion of macrocycles 7 and 8 requires sufficiently drastic
conditions (Caro´s acid in 20% oleum). Clearly, this is
because the diazene fragments of these macrocycles are
electronꢀdeficient due to the strong electronꢀwithdrawꢀ
ing effect of the 1,2,5ꢀoxadiazole rings. It turned out that
the oxidation under these conditions affects all the azo
groups in macrocycles 7 and 8, although being a nonseꢀ
lective process leading to a mixture of isomers. The oxiꢀ
dation of macrocycle 7 gave two isomers with distal or
proximal arrangement of the Nꢀoxide oxygen atoms (comꢀ
pounds 14 and 15). The formation of the mixture of
isomers was confirmed by spectroscopic data: the 13C
NMR spectrum contained eight signals and the 14N NMR
spectrum contained two signals for the azoxy groups at
δ –66.66 and –64.41. The oxidation of macrocycle 8
yielded a more complex mixture of isomeric azoxy derivꢀ
Diamine 3 formed no azo derivatives under the action
of KMnO4 in either water or its mixtures with various
organic solvents. Apparently, this is due to its very low
solubility in the reaction medium. Oxidation of diamine
3 with DBI in acetonitrile gave macrocyclic compound
12. Unfortunately, spectroscopic data for the reaction

Macrocycles from bi(1,2,5ꢀoxadiazoles)
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 3, March, 2008
647
atives represented by structure 16; this was confirmed
by the increased number of signals in its 13C NMR specꢀ
trum (about 30 signals). However, the presence of
a molecular ion peak in the mass spectrum of the oxiꢀ
dized product provided evidence for the oxidation of all
azo groups. It is worth noting that the starting macrocyꢀ
clic compounds 7 and 8 are colored deep red and orange,
respectively, owing to their conjugated double bonds,
while the oxidized products are colorless because
the oxidation of the azo groups into the azoxy groups
breaks the conjugation.
In attempted oxidation of the azo groups in macrocyꢀ
cle 12 or 13, we obtained a complex mixture of inseparaꢀ
ble products. Compound 17 was isolated in the individuꢀ
al state only in the oxidation of macrocycle 11, although
in a low yield (Scheme 4). The complete conversion of
macrocycle 11 was reached under the action of 85% H2O2
in 20% oleum in the presence of Na2WO4•2H2O at 50 °C
for 3 h. According to the mass spectrum of the product
obtained, only one N=N group is oxidized. The number
of signals in the 13C NMR spectrum of compound 17 is
eight (double that of the starting compound). The chemꢀ
ical shifts of the C atom in position 3 of the furoxan
ring bound to the N=N group change only slightly
(from δ 128.89 to 128.82 and 128.90) and one of
the signals for the C atom in position 4 of the furazan ring
also bound to the N=N group is shifted upfield by apꢀ
proximately 3 ppm (from δ 163.19 to 160.30). This is
evidence for the oxidation of the azo group bridging
the furazan rings (Scheme 5).
The yields and selected physicochemical characterisꢀ
tics of the compounds obtained are given in Table 1; their
spectroscopic characteristics are presented in Table 2.
To sum up, we synthesized for the first time macrocyꢀ
clic systems containing alternating azoꢀ and azoxybifuraꢀ
zanyl and ꢀfurazanylfuroxanyl fragments. We found that
the oxidation of 3ꢀaminoꢀ4ꢀ(4ꢀaminoꢀ1,2,5ꢀoxadiazolꢀ
3ꢀyl)ꢀ1,2,5ꢀoxadiazole 2ꢀoxide (2) into azo derivative 9
is a regioselective reaction involving only the NH2 group
in position 3 of the furoxan ring.
Scheme 5

648
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 3, March, 2008
Epishina et al.
Table 1. Yields and selected physicochemical characteristics of the compounds obtained
Comꢀ
pound
Yield (%)
(Method)
M.p./°C
Rf
Found
Calculated
Molecular
formula
(%)
(eluent)*
С
H
N
2
30 (А)
66 (B)
83
164—165
197—198
195—198
0.50 (A)
0.58 (A)
0.32 (A)
0.20 (A)
0.52 (B)
0.47 (B)
0.50 (B)
0.77 (B)
0.28 (B)
0.33 (B)
0.37 (B)
0.36 (B)
0.24 (B)
25.98
26.09
26.18
26.09
31.52
31.38
25.74
25.81
29.00
29.27
29.81
29.27
26.55
26.38
32.22
32.14
26.47
26.66
26.55
26.66
26.51
26.66
26.60
26.66
25.62
25.54
2.24
2.19
2.27
2.19
2.03
1.96
3.14
3.25
—
45.42
45.65
45.51
45.65
45.56
45.74
45.30
45.15
51.41
51.22
50.88
51.22
46.19
46.15
37.68
37.50
46.72
46.68
46.58
46.68
46.53
46.68
46.77
46.68
46.63
44.68
С4H4N6O3
С4H4N6O3
С4H3N5O2
С4H6N6O3
С8N12O4
3
5
55
71
32
28
71
41
6
180—185
(a mixture of isomers)
220—222
7
8
300—303
250—252
199—200
189—191
158—160
137—140
172—175
198—200
—
С12N18O6
С8H4N12O6
С12H8N12O8
С8N12O6
9
1.20
1.11
1.78
1.80
—
10
11
11 (A)
11 (B)
12
12 or 13
14 and 15
16
—
—
—
—
С8N12O6
60
47
5
С8N12O6
С12N18O9
С8N12O7
17
* The eluents are CHCl3—Me2CO (1 : 1) (A) and CH2Cl2—CCl4 (1 : 5) (B).
Table 2. 1H and 13C NMR (DMSOꢀd6), IR, and mass spectra of the compounds obtained
Comꢀ
pound
IR,
ν/cm–1
13C NMR*
1H NMR, δ
[MS, m/z (I (%)]
δ
2
3470, 3340, 1680, 1640, 1610, 1570,
1500, 1460, 1420, 1295, 1070, 1020,
980, 920, 890, 860, 750, 680
122.23 (С(3) furox. ring);
137.09 (С(4) furox. ring);
141.50 (С(3) furaz. ring);
155.12 (С(4) furaz. ring)
6.20 (s, 2 H, NH2); 6.49 (s, 2 H, NH2);
3
3480, 3450. 3300, 1620, 1520, 1480,
1405, 1205, 1120, 1080, 1020, 960,
880
100.83 (С(3) furox. ring);
133.18 (С(4) furox. ring);
154.60, 155,30 (С(3) и С(4)
furaz. ring)
6.41 (s, 2 H, NH2); 6.51 (s, 2 H, NH2)
5
6
3480, 3340, 3280, 2250, 1620, 1600,
1540, 1420, 1350, 1080, 1050, 980,
920
108.20 (CN); 122.51 (С=NOH);
140.51 (C(3) furaz. ring);
154.41 (C(4) furaz. ring)
6.28 (s, 2 H, NH2); 14.80 (br.s, 1 Н,
2 NOH)
3480, 3380, 3350, 3280, 1680, 1660,
1620, 1610, 1580, 1520, 1410, 1380,
1300, 1120, 1070, 960, 920
5.93, 6.17, 6.25, 6.40 (all s, 4 Н, NH2);
7.82, 8.08, 9.77, 12.70 (all s, 2 Н, 2 NOH)
(a mixture of synꢀ and antiꢀisomers)
7
8
1500, 1400, 1370, 1270, 1230, 1110,
1030, 1000, 930, 915, 860
138,82 (С(4) furaz. ring);
163.24 (С(3) furaz. ring)
[328 [M+], 270 (30), 232 (28), 202 (100),
198 (80), 188 (69), 185 (96)]
[492 [M+] (100), 434 (15), 300 (19),
288 (15), 276 (27), 275 (85), 268 (27)]
1450, 1400, 1370, 1230, 1100, 1040,
1000, 915
138,28 (С(4) furaz. ring);
163.28 (С(3) furaz. ring)
(to be continued)

Macrocycles from bi(1,2,5ꢀoxadiazoles)
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 3, March, 2008
649
Table 2. (continued)
Comꢀ
pound
IR,
ν/cm–1
13C NMR*
1H NMR, δ
[MS, m/z (I (%)]
δ
9
3320, 3160, 1620, 1590, 1490, 1470,
1420, 1350, 1220, 1120, 1080, 1050,
1020, 980, 970, 870
128.64 (С(3) furox. ring);
136.89 (С(4) furox. ring);
141.19 (С(3) furaz. ring);
155.52(С(4) furaz. ring)
10
11
3280, 3060, 1700, 1610, 1580, 1500,
1450, 1380, 1320, 1310, 1260, 1210,
1070, 1040, 1000, 980, 890, 860
8.82 (s, 2 H, 2 NH); [238 (4), 224 (22),
211 (20), 210 (90), 195 (4), 182 (20),
180 (14), 169 (16), 168 (100), 153 (16),
138 (14)]
[360 [M+] (100), 345 (28), 331 (90),
329 (25), 315 (20), 300 (10)]
1600, 1410, 1390, 1180, 1050, 1010,
960
128.89 (С(3) furox. ring.);
139.91 (С(4) furox. ring);
141.33 (С(3) furaz. ring);
163.19 (С(4) furaz. ring)
12 or
13
1580, 1500, 1480, 1440, 1415, 1360,
1300, 1260, 1180, 1060, 1030, 1000,
920, 910, 890
101.20 (С(3) furox. ring.);
137.42 (С(4) furox. ring );
162.91, 163.30 (С(3) и С(4)
furaz. ring)
[360 [M+] (10), 330 (8), 300 (30),
180 (70), 168 (100), 152 (40)]
14 and
15
1550, 1510, 1500, 1480, 1440, 1415,
1360, 1300, 1260, 1180, 1060, 1030,
1000, 920, 910, 890
138.77, 139.69, 140.52, 140.72
(С(3) furaz. ring);
153.87, 153.98, 159.70, 159.74
(С(4) furaz. ring )
[360 [M+] (2), 330 (20), 300 (100),
195 (80), 180 (75), 164 (10), 135 (15)]
16
17
1630, 1620, 1480, 1380, 1180, 1110,
1100, 1080, 1020, 1000, 980, 910
About 30 signals:
[540 [M+] (20), 524 (15), 510 (2),
480 (75), 464 (2), 405 (13), 360 (40),
330 (100), 270 (21), 210 (3)]
138—141 ppm (С(3)
furaz. ring), 153—160 ppm
(С(4) furaz. ring)
1650, 1640, 1580, 1500, 1280, 1150,
1040, 980
128.82, 128.90, 139.68, 139.92
(С(3) и С(4) furox. ring);
141.21, 141.32, 160.30, 163
(С(3) и С(4) furaz. ring)
[376 [M+] (23), 360 (100), 346 (18),
344 (12), 330 (53), 300 (35)]
* The signals for the C atoms in the compounds obtained were assigned from the previously derived correlations.4—10,17,18
extracts were dried with MgSO4 and concentrated in a rotary
evaporator. The yield of compound 5 was 4.52 g.
Experimental
2ꢀ(4ꢀAminoꢀ1,2,5ꢀoxadiazolꢀ3ꢀyl)ꢀ1,2ꢀdi(hydroxyimino)ꢀ
ethanamine (6). A solution of nitrile 5 (0.72 g, 4.6 mmol) in
methanol (20 mL) was added to a solution of NaHCO3 (0.48 g,
5.7 mmol) and NH2OH•HCl (0.39 g, 5.5 mmol) in water (7 mL).
The reaction mixture was refluxed for 3 h, the solvent was removed
in a rotary evaporator, and the product was extracted from
the aqueous layer with ethyl acetate (3×10 mL). The extracts were
dried with MgSO4 and concentrated in a rotary evaporator. The yield
of compound 6 was 0.61 g (a mixture of isomers).
3,3´ꢀBiꢀ1,2,5ꢀoxadiazoleꢀ4,4´ꢀdiamine (1). A suspension of
compound 6 (2.0 g, 10.8 mmol) was refluxed in 2 M NaOH (20 mL)
for 1.5 h. On cooling, the precipitate that formed was filtered
off, washed with cold water, and dried in air. The yield of comꢀ
pound 1 was 1.02 g (56%), m.p. 179—180 °C (cf. Ref. 11:
m.p. 180 °C).
IR spectra were recorded on a URꢀ20 spectrometer
(KBr pellets). UV spectra were recorded on a Specord UVꢀVIS
spectrometer in methanol. NMR spectra were recorded on Bruker
WMꢀ250 (1H, 250 MHz) and Bruker AMꢀ300 spectrometers
(
13C, 75.5 MHz; 14N, 21.5 MHz). 1H and 13C chemical shifts were
measured on the δ scale with Me4Si as the internal standard;
14N NMR chemical shifts were measured with MeNO2 as the
external standard. Mass spectra were recorded on a Varian MAT
CHꢀ6 instrument (70 eV). Thinꢀlayer chromatography was carried
out on Silufol UVꢀ254 plates (spots were visualized under UV light).
Caution! The macrocyclic compounds obtained are moderately senꢀ
sitive to mechanical impact and friction and should be handled
carefully.
2ꢀ(4ꢀAminoꢀ1,2,5ꢀoxadiazolꢀ3ꢀyl)ꢀ2ꢀhydroxyiminoacetoniꢀ
trile (5). A solution of 4ꢀaminofurazanꢀ3ꢀcarbohydroximoyl chloꢀ
ride (4) (8.78 g, 54 mmol) in ethyl acetate (500 mL) was added
dropwise at 10 °C to a solution of KCN (7 g, 108 mmol) in water
(80 mL). The reaction mixture was stirred for 8 h; the organic layer
was separated and the aqueous layer was acidified with HCl to pH 7.
The product was extracted with ethyl acetate. The combined organic
3ꢀAminoꢀ4ꢀ(4ꢀaminoꢀ1,2,5ꢀoxadiazolꢀ3ꢀyl)ꢀ1,2,5ꢀoxadiazole
2ꢀoxide (2). A. A solution of K3Fe(CN)6 (1.32 g, 4 mmol) in water
(4 mL) was added at 5—10 °C to a stirred solution of compound 6
(0.37 g, 2 mmol) in a mixture of KOH (0.7 g, 12.5 mmol) and water
(3 mL). After 1 h, the precipitate that formed was filtered off, washed
with water, and dried in air. The product was isolated by preparative

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Russ.Chem.Bull., Int.Ed., Vol. 57, No. 3, March, 2008
Epishina et al.
TLC with CHCl3—acetone (3 : 1) as an eluent. The yield of
compound 2 was 0.11 g.
[1.2.5]oxadiazolo[3,4ꢀc:3´,4´ꢀe:3´´,4´´ꢀi:3´´´,4´´´ꢀk][1,2,7,8]ꢀ
tetraazacyclododecine 3,11ꢀdioxide (13). Under the conditions deꢀ
scribed for the synthesis of compound 11 (method B), compound 12
or 13 (0.34 g) was obtained from diamine 3 (2.95 g, 16 mmol).
Tetrakis[1.2.5]oxadiazolo[3,4ꢀc:3´,4´ꢀe:3´´,4´´ꢀi:3´´´,4´´´ꢀk]ꢀ
[1,2,7,8]tetraazacyclododecine 7,15(16)ꢀdioxides (14 and 15). 20%
Oleum (20 mL) was added to tetrakis[1.2.5]oxadiazolo[3,4ꢀ
c:3´,4´ꢀe:3´´,4´´ꢀi:3´´´,4´´´ꢀk][1,2,7,8]tetraazacyclododecine (7)
(0.98 g, 3 mmol). The reaction mixture was stirred at 50 °C
to complete homogenization. On cooling to 30 °C, 85% H2O2
(2.5 mL) was added dropwise. Then the reaction mixture was stirred
at 80 °C for 1 h, cooled, and poured into water with ice (100 mL).
The precipitate was filtered off, washed with water, dried in air, and
recrystallized from CCl4 to give a mixture of compounds 14 and 15
(0.64 g). UV, λmax/nm: 227 and 270. 14N NMR, δ: –66.66 and
–64.41.
Hexakis[1.2.5]oxadiazolo[3,4ꢀc:3´,4´ꢀe:3´´,4´´ꢀi:3´´´,4´´´ꢀ
k:3´´´´,4´´´´ꢀo:3´´´´´,4´´´´´ꢀq][1,2,7,8,13,14]hexaazacyclooctaꢀ
decine 4(5),12(13),20(21)ꢀtrioxide (16). 20% Oleum (20 mL) was
added to hexakis[1.2.5]oxadiazolo[3,4ꢀc:3´,4´ꢀe:3´´,4´´ꢀi:3´´´,4´´´ꢀ
k:3´´´´,4´´´´ꢀo:3´´´´´,4´´´´´ꢀq][1,2,7,8,13,14]hexaazacyclooctadecine
(8) (0.98 g, 2 mmol). The reaction mixture was stirred at 50 °C
to complete homogenization. On cooling to 30 °C, 85% H2O2
(3.7 mL) was added dropwise. Then the reaction mixture was stirred
at 80 °C for 1 h, cooled to ambient temperature, stirred for 72 h, and
poured into water with ice (100 mL). The precipitate was filtered off,
washed with water, dried in air, and recrystallized from CCl4.
The yield of compound 16 was 0.51 g.
Tetrakis[1.2.5]oxadiazolo[3,4ꢀc:3´,4´ꢀe:3´´,4´´ꢀi:3´´´,4´´´ꢀk]ꢀ
[1,2,7,8]tetraazacyclododecine 1,7,14ꢀtrioxide (17). 20% Oleum
(20 mL) was added to tetrakis[1.2.5]oxadiazolo[3,4ꢀc:3´,4´ꢀ
e:3´´,4´´ꢀi:3´´´,4´´´ꢀk][1,2,7,8]tetraazacyclododecine 1,14ꢀdioxide
(10) (0.97 g, 2.7 mmol). The reaction mixture was stirred at 50 °C
to complete homogenization. On cooling to 30 °C, 85% H2O2
(3.0 mL) was added dropwise. Then the reaction mixture was heated
to 50 °C and Na2WO4•2H2O (1.62 g, 5.4 mmol) was carefully
added in portions. The reaction mixture was stirred for 3 h, cooled
to ambient temperature, and poured into water with ice (100 mL).
The precipitate was filtered off, washed with water, and dried in air.
The yield of compound 17 was 0.05 g.
B. A 2 M solution of HCl (1.5 mL) was added to a suspension of
compound 6 (0.50 g, 2.7 mmol) in water (3 mL). Then a solution of
bromine (0.43 g, 2.7 mmol) in conc. HCl (2 mL) was added
dropwise at 5—10 °C. After 20 min, the precipitate that formed was
filtered off, washed with water, and dried in air. The yield of
compound 2 was 0.30 g.
4ꢀAminoꢀ3ꢀ(4ꢀaminoꢀ1,2,5ꢀoxadiazolꢀ3ꢀyl)ꢀ1,2,5ꢀoxadiazole
2ꢀoxide (3). A suspension of compound 2 (0.30 g, 1.6 mmol) was
refluxed in dioxane for 5 h. The solvent was removed in a rotary
evaporator and the product was isolated by preparative TLC with
CHCl3—acetone (3 : 1) as an eluent. The yield of compound 3
was 0.25 g.
4,4´ꢀBis(4ꢀaminoꢀ1,2,5ꢀoxadiazolꢀ3ꢀyl)ꢀ3,3´ꢀazo(1,2,5ꢀoxaꢀ
diazole 2ꢀoxide) (9). Hydrochloric acid (30 mL) was added at
18—20 °C to a suspension of diamine 2 (1.0 g, 5.4 mmol) in acetone
(20 mL). Then a solution of KMnO4 (0.87 g, 5.4 mmol) in water
(54 mL) was added dropwise at the same temperature. The reaction
mixture was stirred for 30 min until it became colorless; the resulting
precipitate was filtered off, washed with water, and dried in air.
The yield of compound 9 was 0.71 g.
4,4´ꢀBis(4ꢀacetylaminoꢀ1,2,5ꢀoxadiazolꢀ3ꢀyl)ꢀ3,3´ꢀazo(1,2,5ꢀ
oxadiazole 2ꢀoxide) (10). Acetic anhydride (10 mL) was added to
compound 9 (1 g, 2.74 mmol). The mixture was stirred for 30 min,
acidified with two drops of conc. H2SO4, and stirred again for an
additional 30 min. The precipitate was filtered off, washed with
water, and dried in air. The yield of compound 10 was 0.50 g.
Tetrakis[1.2.5]oxadiazolo[3,4ꢀc:3´,4´ꢀe:3´´,4´´ꢀi:3´´´,4´´´ꢀ
k][1,2,7,8]tetraazacyclododecine (7) and hexakis[1.2.5]oxadiazoꢀ
lo[3,4ꢀc:3´,4´ꢀe:3´´,4´´ꢀi:3´´´,4´´´ꢀk:3´´´´,4´´´´ꢀo:3´´´´´,
4´´´´´ꢀq][1,2,7,8,13,14]hexaazacyclooctadecine (8). Dibroꢀ
moisocyanurate (20 g, 140 mmol) prepared according to a known
procedure19 was added to a stirred suspension of 3,3´ꢀbiꢀ1,2,5ꢀ
oxadiazoleꢀ4,4´ꢀdiamine 1 (5.88 g, 35 mmol) in MeCN (500 mL).
The reaction mixture was kept for 48 h. The excess DBI was filtered
off and the solvent was removed in a rotary evaporator. The products
were isolated by preparative column chromatography on silica gel
(40/100 µ) with CH2Cl2—CCl4 (1 : 5) as an eluent. The yield of
compound 7 was 1.87 g, red crystals. UV, λmax/nm: 227 and 370.
The yield of compound 8 was 1.61 g, orange crystals.
Tetrakis[1.2.5]oxadiazolo[3,4ꢀc:3´,4´ꢀe:3´´,4´´ꢀi:3´´´,4´´´ꢀk]ꢀ
[1,2,7,8]tetraazacyclododecine 1,14ꢀdioxide (11). A. Dibromoisoꢀ
cyanurate (8.5 g, 60 mmol) was added to a stirred solution of
compound 9 (4.37 g, 12 mmol) in MeCN (500 mL). The reaction
mixture was kept for 33 h. The excess DBI was filtered off and
the solvent was removed in a rotary evaporator. Dichloromethane
(200 mL) was added and DBI was filtered off again. The solvent was
removed and the product was isolated by preparative column chroꢀ
matography on silica gel (40/100 µ) with CH2Cl2—CCl4 (1 : 5) as
an eluent. The yield of compound 11 was 0.45 g.
B. Dibromoisocyanurate (8.20 g, 58 mmol) was added to
a stirred suspension of compound 2 (2.95 g, 16 mmol) in MeCN
(300 mL). The reaction mixture was kept for 72 h. The excess DBI was
filtered off and the solvent was removed in a rotary evaporator. Diꢀ
chloromethane (200 mL) was added and DBI was filtered off again.
The solvent was removed and the product was isolated by preparative
column chromatography on silica gel (40/100 µ) with CH2Cl2—CCl4
(1 : 5) as an eluent. The yield of compound 11 was 0.32 g.
Tetrakis[1.2.5]oxadiazolo[3,4ꢀc:3´,4´ꢀe:3´´,4´´ꢀi:3´´´,4´´´ꢀk]ꢀ
[1,2,7,8]tetraazacyclododecine 3,12ꢀdioxide (12) or tetrakisꢀ
References
1. N. N. Makhova, T. I. Godovikova, Zh. Ross. Khim. Oꢀva im.
D.I. Mendeleeva, 1997, 41, 54 [Mendeleev Chem. J., 1997, 41,
81 (Engl. Transl.)].
2. A. B. Sheremetev, N. N. Makhova, W. Friedrichsen, Adv.
Heterocycl. Chem., 2001, 78, 66.
3. N. N. Makhova, I. V. Ovchinnikov, A. S. Kulikov, S. I. Moloꢀ
tov, E. L. Baryshnikova, Pure Appl. Chem., 2004, 76, 1691.
4. V. E. Eman, M. S. Sukhanov, O. V. Lebedev, L. V. Batog, L. S.
Konstantinova, V. Yu. Rozhkov, L. I. Khmel´nitskii, Mendeleev
Commun., 1996, 66.
5. L. V. Batog, L. S. Konstantinova, O. V. Lebedev, L. I.
Khmel´nitskii, Mendeleev Commun., 1996, 193.
6. L. V. Batog, L. S. Konstantinova, V. E. Eman, M. S. Sukhanov,
A. S. Batsanov, Yu. T. Struchkov, O. V. Lebedev, L. I.
Khmel´nitskii, Khim. Geterotsikl. Soedin., 1996, 406 [Chem.
Heterocycl. Compd., 1996 (Engl. Transl.)].
7. L. V. Batog, V. Yu. Rozhkov, L. S. Konstantinova, V. E. Eman,
M. O. Dekaprilevich, Yu. T. Struchkov, S. E. Semenov, O. V.

Macrocycles from bi(1,2,5ꢀoxadiazoles)
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 3, March, 2008
651
Lebedev, L. I. Khmel´nitskii, Izv. Akad. Nauk, Ser. Khim.,
1996, 1250 [Russ. Chem. Bull., 1996, 45, 1189 (Engl. Transl.)].
8. V. E. Eman, M. S. Sukhanov, O. V. Lebedev, L. V. Batog, L. S.
Konstantinova, V. Yu. Rozhkov, M. O. Dekaprilevich, Yu. T.
Struchkov, L. I. Khmel´nitskii, Mendeleev Commun., 1997, 5.
9. A. B. Sheremetev, O. V. Kharitonova, Mendeleev Commun.,
1992, 157.
15. M. A. Epishina, N. N. Makhova, L. V. Batog, L. S. Konstantiꢀ
nova, L. I. Khmel´nitskii, Mendeleev. Commun., 1994, 102.
16. L. Chertanova, C. Pascard, A. B. Sheremetev, Supramol. Chem.,
1993, 3, 71.
17. A. S. Kulikov, I. V. Ovchinnikov, S. I. Molotov, N. N. Makhoꢀ
va, Izv. Akad. Nauk, Ser. Khim., 2003, 1727 [Russ. Chem. Bull.,
Int. Ed., 2003, 52, 1822].
10. A. B. Sheremetev, E. V. Shatunova, B. B. Averkiev, D. E.
Dmitriev, V. A. Petukhov, M. Yu. Antipin, Heteroatom. Chem.,
2004, 15, 131.
11. M. D. Coburn, J. Heterocycl. Chem., 1968, 5, 83; J. Labelled
Compds Radiopharm., 1985, 22, 183.
18. I. V. Ovchinnikov, N. N. Makhova, L. I. Khmel´nitskii, V. S.
Kuz´min, L. N. Akimova, V. I. Pepekin, Dokl. Akad. Nauk,
1998, 359, 499 [Dokl. Chem., 359, 67 (Engl. Transl.)].
19. Z. P. Demko, P. B. Zachary, M. Bartsch, K. B. Sharpless, Org.
Lett., 2000, 2, 2221.
12. A. B. Sheremetev, E. V. Mantseva, Mendeleev Commun.,
1996, 246.
13. T. Ishikawa, J. Heterocycl. Chem., 1965, 2, 253; R. Beaudegꢀ
nies, S. Wendebom, Heterocycles, 2003, 60, 2417.
14. V. N. Yarovenko, M. M. Krayushkin, O. V. Lysenko, L. M.
Kustov, I. V. Zavarzin, Izv. Akad. Nauk, Ser. Khim., 1994, 444
[Russ. Chem. Bul., 1994, 43, 402 (Engl. Transl.)].
Received November 1, 2007;
in revised form December 20, 2007