Synthesis of novel 14-membered cyclic bis-semicarbazones

Article abstract of DOI:10.1016/j.tetlet.2014.08.016

An efficient method for the stereoselective synthesis of novel 14-membered cyclic bis-semicarbazones based on acid-catalyzed cyclization of the hydrazones of 3-(3-oxobutyl)semicarbazides has been developed. The starting semicarbazides were prepared according to a four-step strategy involving amidoalkylation of the sodium enolate of acetylacetone with N-(α-tosylbenzyl)carbamates followed by base-promoted retro-Claisen reaction and treatment of the obtained N-(3-oxobutyl)carbamates with hydrazine.

Full text of DOI:10.1016/j.tetlet.2014.08.016

Tetrahedron Letters 55 (2014) 5481–5485
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Tetrahedron Letters
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Synthesis of novel 14-membered cyclic bis-semicarbazones
a,
⇑
a
a
b
Anatoly D. Shutalev , Anastasia A. Fesenko , Olesya M. Kuzmina , Alexander N. Volov ,
Dmitry V. Albov , Vladimir V. Chernyshev , Ilia A. Zamilatskov b
c
b,c
a
Department of Organic Chemistry, Moscow State University of Fine Chemical Technologies, 86 Vernadsky Avenue, 119571 Moscow, Russian Federation
A. N. Frumkin Institute of Physical Chemistry and Electrochemistry RAS, 31 Leninsky Prospect, 119071 Moscow, Russian Federation
Department of Chemistry, M. V. Lomonosov Moscow State University, 1-3 Leninskie Gory, 119991 Moscow, Russian Federation
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 May 2014
Revised 3 July 2014
Accepted 6 August 2014
Available online 13 August 2014
An efficient method for the stereoselective synthesis of novel 14-membered cyclic bis-semicarbazones
based on acid-catalyzed cyclization of the hydrazones of 3-(3-oxobutyl)semicarbazides has been
developed. The starting semicarbazides were prepared according to a four-step strategy involving amido-
alkylation of the sodium enolate of acetylacetone with N-(a-tosylbenzyl)carbamates followed by base-
promoted retro-Claisen reaction and treatment of the obtained N-(3-oxobutyl)carbamates with
hydrazine.
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Amidoalkylation
retro-Claisen reaction
Semicarbazides
Cyclic semicarbazones
Azamacrocycles
Monocyclic semicarbazones (A, Fig. 1), particularly 5- and
6
-membered representatives, are of current interest due to their
multifaceted biological properties. For example, 2,4-dihydro-3H-
,2,4-triazol-3-ones 1 are antagonists of the angiotensin AII recep-
1
1
2
tor and human-type neurokinin1 receptor. These compounds
possess antimicrobial, anticonvulsant,4 anticancer,5 antifungal,
3
6
7
and herbicidal activities. A wide range of biological effects of
2
Figure 1. General formula of heterocyclic semicarbazones A and their five-, six- and
seven-membered representatives 1–3.
8
,3,4,5-tetrahydro-1,2,4-triazin-3-ones 2 have been reported.
9
10
The high synthetic accessibility of compounds 1 and 2 is crucial
for their versatile applications in medicine and agriculture. In con-
trast, the biological activities of seven-membered monocyclic
semicarbazones, 2,4,5,6-tetrahydro-3H-1,2,4-triazepin-3-ones 3,
and monocyclic semicarbazones with larger ring sizes, remain
unknown due to a lack of simple general approaches to these
compounds.
to compounds 3 is desirable for both synthetic and medicinal
chemistry.
We hypothesized that 2-unsubstituted triazepinones 3 could be
obtained by intramolecular cyclization of (
c-oxoalkyl)semicarbaz-
ides 4, prepared by substitution of the alkoxy group in carbamates
In continuation of our research on the synthesis of 1,3-diazepin-
5
by treatment with hydrazine (Scheme 1).
1
1
2
-ones, we were interested in the preparation of their aza-ana-
Compounds 5 can be synthesized by aza-Michael addition of
logs, cyclic semicarbazones 3. To date, only a few compounds of
type 3 have been synthesized according to the reported procedures
based on the reaction of 4-isocyanato-4-methylpentan-2-one with
15
carbamates to enones, Mannich condensation of aldehydes with
16
methyl ketones and carbamates, reactions of N-alkoxycarbonyli-
17
mines with ketones, etc. The main drawbacks of the reported
1
2
methylhydrazine, oxidation of 5,5,7-trimethyl-2,4,5,6-tetrahy-
syntheses that strongly reduce their preparative value are small-
scale preparations and the use of chromatography for isolation of
the target products. We supposed that compounds 5 could be
obtained by retro-Claisen reaction of carbamates 6, which could
be readily synthesized following our previously reported approach
13
dro-3H-1,2,4-triazepine-3-thione, or cyclizations of two semicar-
1
4
bazones. Thus, the development of a new and general approach
⇑
Corresponding author. Tel.: +7 495 936 8908; fax: +7 495 936 8909.
E-mail address: shutalev@orc.ru (A.D. Shutalev).
1
8
based on amidoalkylation reactions.
http://dx.doi.org/10.1016/j.tetlet.2014.08.016
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
0

5
482
A. D. Shutalev et al. / Tetrahedron Letters 55 (2014) 5481–5485
Scheme 1. Retrosynthesis of seven-membered cyclic semicarbazones 3.
Here we report the three-step synthesis of two examples of car-
bamates 5 on multigram scale via the preparation of carbamates 6
followed by retro-Claisen condensation, and the reaction of com-
pounds 5 with hydrazine to provide the hydrazones of semicarbaz-
ides 4. The results of the acid-catalyzed heterocyclizations of
these hydrazones, which unexpectedly gave 14-membered cyclic
bis-semicarbazones instead of seven-membered cyclic semicarba-
zones 3, are described.
Scheme 3. Synthesis of the hydrazones of N-(3-oxobutyl)semicarbazides 14a,b.
The starting amidoalkylation reagents, ethyl N-(
a-tosylben-
Since the formation of semicarbazide 14a in the reaction of 12a
with hydrazine in EtOH, n-BuOH and Py did not proceed, refluxing
hydrazine or hydrazine hydrate was used as the solvent and
reagent to induce the substitution of the ethoxy group. Under these
conditions the formation of azine 16 was completely suppressed,
and gradual transformation of the intermediate hydrazone 13a
into semicarbazide 14a (a mixture of E- and Z-isomers) was
observed (Table 1; entries 7–9, 13). This transformation was prac-
tically complete in 24 h. Dihydropyrazole 17 resulting from elimi-
nation of semicarbazide in 14a followed by ring closure was the
major by-product formed in the reaction with hydrazine hydrate.
Refluxing hydrazine gave the best results. Only 6% of dihydropy-
razole 17 was observed after 20 h (entry 13), and semicarbazide
zyl)carbamates 7a,b, were obtained by our convenient modifica-
1
8
19
tion
of Engberts method
using p-toluenesulfinic acid (8)
instead of sodium p-toluenesulfinate in the presence of formic acid.
The three-component condensation of ethyl carbamate (9) with
aldehydes 10a,b and sulfinic acid 8 proceeded in water at 70 °C
for 1–1.35 h to give the corresponding sulfones 7a,b in 88% and
1% yields, respectively (Scheme 2).20
7
Reaction of sulfones 7a,b with the sodium enolate of acetylace-
tone proceeded readily in dry MeCN at room temperature for eight
hours to afford the products of nucleophilic substitution of the
tosyl group, that is, carbamates 11a,b, in 93% and 91% yields,
respectively (Scheme 2).21 Ethyl N-(3-oxobutyl)carbamates 12a,b
were prepared in high yields from 11a,b by retro-Claisen reaction
1
2 4
4a was isolated in 52% yield. Under optimal conditions (N H ,
using an aqueous solution of KOH (5 equiv) at room temperature
23
2
2
reflux, 23.5 h), compound 14a was obtained in 60% yield. Simi-
larly, compound 14b was prepared in 65% yield from carbamate
12b.
for three hours.
Next, we studied the reaction of carbamate 12a with hydrazine
2
3
1
under various conditions using H NMR spectroscopy. This reaction
The crude semicarbazides 14a,b were isolated as mixtures of E-
and Z-isomers with significant predominance of one of them (up to
was found to proceed in two sequential steps involving a relatively
fast formation of hydrazone 13a followed by slow substitution of
the ethoxy group resulting in the target hydrazone of semicarbaz-
ide 14a (Scheme 3, Table 1). The latter could be readily isolated
from the reaction mixtures after evaporation of all the volatiles
under reduced pressure and treatment of the residues with ether
in which compound 14a was poorly soluble.
The reaction of 12a with hydrazine hydrate or hydrazine in dif-
ferent solvents (EtOH, n-BuOH, Py) at room temperature or at
reflux gave mixtures of hydrazone 13a and azine 16 (Table 1;
entries 1–6, 11 and 12). The amount of azine 16 decreased with
an increase in the reaction time (entry 1 vs entry 2), the use of
9
0%). Their configuration could not be determined unambiguously
1
1
using a H– H NOESY experiment in DMSO-d
ison of the experimental carbon chemical shifts for the CH
CH groups of the CH C(@NNH )CH moiety in 14a with those cal-
6
. However, compar-
2
and
3
2
2
3
culated by the GIAO method at the RHF/6-311+G(2d,p) level using
the DFT-B3LYP/6-31+G(d,p) optimized geometries for both (E)-14a
and (Z)-14a clearly demonstrated that the major isomer of 14a had
the (E)-configuration. The DFT calculations at the B3LYP/6-
3
1+G(d,p) level also showed that the (E)-isomer of 14a was more
1
stable (1.91 kcal/mol in DMSO) than the (Z)-isomer. Since the
H
1
3
and C NMR spectra of the major isomers of 14a and 14b were
similar, we concluded that the major isomer of 14b also had the
(E)-configuration.
2 4
an excess of N H (entry 2 vs entry 3), and when alcohols were
used as solvents instead of pyridine (entries 3–6 vs entry 12).
1
According to H NMR spectroscopic data, hydrazone 13a was
Finally, we studied the heterocyclization of 14a,b under acidic
conditions expecting the formation of triazepinones 18a,b via
formed as a mixture of E- and Z-isomers, and azine 16 was a mix-
ture of stereoisomers (up to 8) with significant predominance of
two of them (Table 1).
1
5a,b (Scheme 4). Surprisingly, reflux of 14a,b in EtOH in the pres-
ence of TsOH (1.2 equiv) gave 14-membered cyclic bis-semicarba-
2
4
zones 19a,b in 71% and 80% yields, respectively, instead of
triazepinones 18a,b. Compound 19a was also prepared in 70% yield
in refluxing MeCN.
Compounds 19a,b were formed as white solids which were
practically insoluble (especially 19b) in common solvents includ-
ing DMSO, DMF, etc. The structure of 19a was established by IR,
1
13
H and C NMR spectroscopy, mass spectrometry, and powder
2
5
X-ray diffraction. It was difficult to record satisfactory NMR spec-
tra of 19b due to its extremely low solubility. Therefore, solid-state
1
5
13
N and C NMR spectra were acquired. This compound was also
characterized by IR spectroscopy, mass spectrometry, and powder
2
5
X-ray diffraction. The crystal structures of 19a,b are shown in the
Scheme 2. Synthesis of ethyl N-(3-oxoalkyl)carbamates 12a,b.
Supplementary Information.

A. D. Shutalev et al. / Tetrahedron Letters 55 (2014) 5481–5485
5483
Table 1
Product distribution upon reaction of carbamate 12a with hydrazine
a
Entry
Reagent
Equiv of N
2
H
4
Solvent
Conc of 12a (mmol/mL)
Reaction conditions
Product distributionb (%)
1
3a (E/Z)c
14a (E/Z)c
16d
17
1
2
3
4
5
6
N
N
N
N
N
N
N
N
N
N
N
N
N
H
2 4
H
2 4
H
2 4
H
2 4
H
2 4
H
2 4
H
2 4
H
2 4
H
2 4
H
2 4
H
2 4
H
2 4
H
2 4
ÁH
2
ÁH
2
ÁH
2
ÁH
2
ÁH
2
ÁH
2
ÁH
2
ÁH
2
ÁH
2
ÁH
2
O
O
O
O
O
O
O
O
O
O
3
3
10
10
10
10
41
105
105
103
11
EtOH
EtOH
EtOH
EtOH
EtOH
n-BuOH
—
—
—
—
0.40
0.40
0.36
0.36
0.36
0.33
0.50
0.20
0.20
0.20
0.30
0.30
0.36
Reflux, 5 h
Reflux, 10 h
Rt, 11 h
76 (86/14)
85 (87/13)
90 (88/12)
86 (88/12)
87 (85/15)
90 (87/13)
39 (87/13)
32 (84/16)
Trace
0
0
0
0
0
0
24
15
10
14
13
10
0
0
0
0
0
0
0
0
0
Reflux, 5 h 20 min
Reflux, 10 h 50 min
Reflux, 5 h 15 min
Reflux, 10 h 40 min
Reflux, 10 h 20 min
Reflux, 24 h
Reflux, 36 h 25 min
Reflux, 2 h 35 min
Reflux, 12 h
0
e
7
46 (84/16)
55 (84/16)
87 (84/16)
39 (81/19)
0
15
13
13
61
0
8
9
f
10
11
12
13
0
Pyridine
Pyridine
—
87 (87/13)
37 (86/14)
13 (85/15)
13
63
0
11
88
0
0
6
g
Reflux, 20 h
81 (84/16)
a
In all cases the starting material was completely consumed.
According to the 1H NMR spectra of the crude products obtained after evaporation of the reaction mixtures in vacuo to dryness, co-evaporation of the residues with
b
toluene (2–4 times) and drying in vacuo. The amounts of azine 16 in mixtures with 13a were determined by comparison of the integral intensities of the NH
with those of the OCH or CH signals for 13a plus 16.
2
signals for 13a
2
3
c
E/Z isomer ratios are given in parentheses.
Mixtures of stereoisomers.
Compound 14a was isolated in a 31% yield after evaporation of the reaction mixture in vacuo to dryness followed by treatment with Et
Unidentified products were observed in the H NMR spectrum along with 14a and 17.
d
e
f
2
O and filtration.
O and filtration.
1
g
Compound 14a was isolated in a 52% yield after evaporation of the reaction mixture in vacuo to dryness followed by treatment with Et
2
Scheme 4. Acid-catalyzed transformation of semicarbazides 14a,b into 14-mem-
bered macrocyclic bis-semicarbazones 19a,b.
Since macrocycle 19a has two distant chiral centers, we
expected it to form as a mixture of two diastereomers in approxi-
mately equal amounts. However, according to NMR spectra and
X-ray analysis, only a single diastereomer of 19a with trans-
orientation of the phenyl groups was obtained. Thus, the formation
of 19a via intermediate 20a could be excluded (Scheme 5).
Scheme 5 shows a plausible pathway for the transformation of
Scheme 5. A plausible pathway for the transformation of 14a,b into macrocycles
9a,b.
1
1
4a into macrocycle 19a, including acid-catalyzed elimination of
semicarbazide 22 resulting in unsaturated hydrazone 21a followed
by the formation of semicarbazone 23a. Dimerization of compound
involving two molecules of the starting material provides an effi-
cient stereoselective access to novel 14-membered cyclic bis-semi-
carbazones. The starting semicarbazides were readily prepared
according to our original four-step approach involving amidoalkyl-
2
6
2
2
3a via intermolecular aza-Michael addition affords intermediate
4a which cyclizes through an intramolecular aza-Michael reac-
tion to give the final product 19a. Most probably, cyclization of
4a is controlled by the presence of the phenyl group at the chiral
center to give exclusively the trans-isomer of 19a.
ation of the sodium enolate of acetylacetone with N-(a-tosylben-
2
zyl)carbamates followed by base-promoted retro-Claisen reaction
and treatment of the obtained N-(3-oxobutyl)carbamates with
hydrazine. We hope that the obtained class of heterocycles could
be of interest from various viewpoints, in particular, as new poly-
aza macrocyclic ligands for metal complexes.
According to powder X-ray analysis, the crystallized macrocycle
1
9b was also a single diastereomer with trans-orientation of the
aryl groups. Because of the extremely low solubility of analytically
pure 19b, attempts to record its NMR spectra in solutions failed.
1
However, the H NMR spectrum (8489 scans) of a saturated
Acknowledgments
6
solution of crude 19b in DMSO-d showed two sets of signals of
trans- and cis-isomers in a ratio of 91:9. Therefore, we suppose that
compound 19b was similarly formed with high stereoselectivity
according to the pathway shown in Scheme 5.
In summary, we have demonstrated that the acid-catalyzed
cyclization of the hydrazones of 3-(3-oxobutyl)semicarbazides
This research was financially supported by the Ministry of
Education and Science of the Russian Federation (project part of
government order, 4.1849.2014/K) and the Presidential Grant for
Young Scientists (MK-2956.2013.3). We thank Dr. Pavel A. Soloviev
for recording the NMR spectra.

5
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A. D. Shutalev et al. / Tetrahedron Letters 55 (2014) 5481–5485
total. After completion of the reaction, the obtained suspension was cooled to
°C. The precipitate was filtered, washed with ice-cold H O and petroleum
Supplementary data
0
2
ether, and dried to give carbamate 7a (15.622 g, 88%) as a white solid which
was used without additional purification.
Synthesis of ethyl N-[(4-methylphenyl)(tosyl)methyl]carbamate (7b): Compound
Supplementary data (copies of IR, H and 13C NMR spectra of all
1
the synthesized compounds, powder X-ray structural data for
9a,b, and computational data) associated with this article can
7b (22.210 g, 71%, white solid) was prepared from 4-methylbenzaldehyde
1
(
10.090 g, 83.97 mmol), p-toluenesulfinic acid (8) (13.125 g, 84.01 mmol) and
be found, in the online version, at http://dx.doi.org/10.1016/j.tet-
let.2014.08.016. These data include MOL files and InChiKeys of
the most important compounds described in this article.
ethyl carbamate (9) (7.856 g, 88.17 mmol) in H
as described for 7a.
2
O (166 mL) (70 °C, 1 h 20 min)
2
2
2
1. Synthesis of ethyl N-[(2-acetyl-3-oxo-1-phenyl)but-1-yl]carbamate (11a): To a
cooled (ice-cold bath) stirred suspension of NaH (0.316 g, 13.18 mmol) in dry
MeCN (10 mL) was added a solution of acetylacetone (1.341 g, 13.39 mmol) in
MeCN (12 mL), and the resulting mixture was stirred for 30 min. The ice-bath
was removed, and to the obtained suspension were added sulfone 7a (4.007 g,
References and notes
1
2.02 mmol) and MeCN (4 mL). The mixture was stirred at room temperature
for 8 h, and the solvent was removed in vacuo. The oily residue was triturated
with saturated aqueous NaHCO (10 mL) and petroleum ether (10 mL), and the
obtained suspension was left overnight at room temperature and cooled to
°C. The precipitate was filtered, washed with ice-cold H O and petroleum
ether, and dried to give compound 11a (3.099 g, 93%) as a white solid. Mp
1
.
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2
3
Zingaro, G. J.; Siegl, P. K. S.; Kivlighn, S. D.; Lotti, V. J.; Chang, R. S. L.; Greenlee,
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0
2
7a
100.5–101.5 °C (EtOH–H
2
O, 1:1) (lit.1
mp 87–88 °C). Anal. Calcd for
C
15
H
19NO : C, 64.97; H, 6.91; N, 5.05. Found: C, 64.98; H, 6.97; N, 5.26.
4
2
.
Tattersall, F. D.; Rycroft, W.; Francis, B.; Pearce, D.; Merchant, K.; MacLeod, A.
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Synthesis of ethyl N-{[2-acetyl-1-(4-methylphenyl)-3-oxo]but-1-yl}carbamate
11b): Compound 11b (3.270 g, 91%, white solid) was prepared from
acetylacetone (1.270 g, 12.67 mmol), NaH (0.299 g, 12.46 mmol) and sulfone
b (4.230 g, 12.38 mmol) in MeCN (26 mL) (rt, 9 h 30 min) as described for 11a.
Note: the reaction was carried out in a 50 mL round-bottomed flask, the
(
1
996, 35, 1121–1129.
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7
(
3
4
.
.
4
reaction mixture was transferred into a 250 mL round-bottomed flask prior to
evaporation since the vigorous foam formation during the evaporation
complicated removal of the solvent when the flask of lower volume was
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(a) Shu, B.; Zheng, Y.; Wang, S.-B.; Deng, X.-Q.; Quan, Z.-S. Arch. Pharm. Chem.
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used). Mp 94–95 °C (EtOH–H
.27; N, 4.81. Found: C, 65.69; H, 7.15; N, 4.82.
2. Synthesis of ethyl N-[(3-oxo-1-phenyl)but-1-yl]carbamate (12a): To a solution of
KOH (5.269 g, 93.91 mmol) in H O (90 mL) was added carbamate 11a (5.150 g,
8.57 mmol) and the obtained mixture was stirred at room temperature. An
2 4
O, 1:1). Anal. Calcd for C16H21NO : C, 65.96; H,
7
33, 2772–2777.
2
5
6
.
.
Kattimani, P. P.; Kamble, R. R.; Kariduraganavar, M. Y.; Dorababu, A.; Hunnur, R.
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emulsion formed at the beginning of stirring, and after approximately 50 min,
the oily substance started to solidify and was triturated immediately [since at
the beginning of the solidification this was easy to do (soft material),
otherwise, the material becomes too hard to be easily triturated]. The
obtained suspension was stirred for an additional 2 h 10 min (the overall
reaction time was 3 h). After completion of the reaction the obtained
suspension was cooled to 0 °C. The precipitate was filtered, washed with ice-
4
0–79; (b) Heeres, J.; Backx, L. J. J.; Van Cutsem, J. J. Med. Chem. 1984, 27, 894–
9
00.
7
8
.
.
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2
000, 63, 777–781; (c) Dayan, F. E.; Armstrong, B. M.; Weete, J. D. J. Agric. Food
cold H
2
O and petroleum ether, and dried to give compound 12a (3.644 g, 83%)
white solid. Mp 52.5–56.5 °C (EtOH–H
O, 1:3).27 Anal. Calcd for
17NO : C, 66.36; H, 7.28; N, 5.95. Found: C, 66.38; H, 7.29; N, 6.02.
Chem. 1998, 46, 2024–2029.
(a) Kelly, M. J.; Jacobson, R. M. U.S. Patent 6,995,157, 2006; Chem. Abstr. 2002,
as
a
2
C
13
H
3
137, 109298.; (b) Nagato, S.; Kawano, K.; Ito, K.; Norimine, Y.; Ueno, K.; Hanada,
Synthesis of ethyl N-{[1-(4-methylphenyl)-3-oxo]but-1-yl}carbamate (12b): Com-
pound 12b (2.972 g, 91%, white solid) was prepared from carbamate 11b
T.; Amino, H.; Ogo, M.; Hatakeyama, S.; Ueno, M.; Groom, A.; Rivers, L.; Smith,
T. Patent Application US 2006/0189622, 2006; Chem. Abstr. 2002, 136, 263177.;
(
2
3.597 g, 12.35 mmol) and KOH (2.926 g, 52.14 mmol) in H O (60 mL) (rt, 3 h)
(
c) Miki, H.; Iwanaga, K.; Matsuno, T.; Aoki, I. U.S. Patent 5,994,355, 1999;
as described for 12a. An analytically pure sample (0.285 g) was obtained from
crude 12b (0.362 g) using column chromatography on silica gel 60 (6.25 g)
eluting with petroleum ether–CHCl (from 3:1 to 1:2) followed by trituration
3
of the concentrated main fraction with hexane until complete crystallization,
which was followed by filtration, washing with hexane and drying under high
Chem. Abstr. 1997, 126, 8142.; (d) Haikala, H. O.; Honkanen, E. J.; Lonnberg, K.
K.; Nore, P. T.; Pystynen, J. J.; Luiro, A. M.; Pippuri, A. K. U.S. Patent 5,122,524,
1
1
992; Chem. Abstr. 1991, 114, 228967.; e Kristinsson, H. U.S. Patent 4,931,439,
990; Chem. Abstr. 1989, 111, 232868.
9
.
Temple, C. Triazoles 1,2,4 In The Chemistry of Heterocyclic Compounds;
vacuum (0.1 mmHg). Mp 57–58 °C. Anal. Calcd for C14
.68; N, 5.62. Found: C, 67.44; H, 7.70; N, 5.69.
3. Synthesis of the hydrazone of 3-[(3-oxo-1-phenyl)but-1-yl]semicarbazide (14a): A
solution of compound 12a (2.060 g, 8.76 mmol) in N (23 mL) was refluxed
3
H19NO : C, 67.45; H,
Montgomery, J. A., Ed.; John Wiley: New York, 1981; Vol. 37,.
7
1
1
0. Neunhoeffer, H. 1,2,4-Triazines In The Chemistry of Heterocyclic Compounds;
Weissberger, A., Taylor, E., Eds.; John Wiley: New York, 1978; Vol. 33,.
1. (a) Fesenko, A. A.; Shutalev, A. D. Tetrahedron Lett. 2014, 55, 1416–1420; (b)
Fesenko, A. A.; Trafimova, A. A.; Shutalev, A. D. Org. Biomol. Chem. 2012, 10,
2 4
H
under stirring for 23 h 30 min. At the beginning of reflux, the mixture was
flushed with Ar. A drying tube containing KOH was used to protect the reaction
mixture from air moisture and CO . After completion of the reaction, N H was
2 2 4
4
47–462; (c) Fesenko, A. A.; Shutalev, A. D. Tetrahedron 2011, 67, 6876–6882;
(
d) Fesenko, A. A.; Trafimova, L. A.; Cheshkov, D. A.; Shutalev, A. D. Tetrahedron
removed in vacuo (the temperature of the bath was about 60 °C) until a white
Lett. 2010, 51, 5056–5059; (e) Fesenko, A. A.; Tullberg, M. L.; Shutalev, A. D.
Tetrahedron 2009, 65, 2344–2350; (f) Shutalev, A. D.; Fesenko, A. A.; Cheshkov,
D. A.; Goliguzov, D. V. Tetrahedron Lett. 2008, 49, 4099–4101.
oily residue remained, which was co-evaporated with toluene (4 Â 10 mL). The
obtained solid was suspended in Et
precipitate was filtered, washed with Et
2
O (15 mL) and cooled (À18 °C). The
2
O, and dried. The obtained solid
1
1
1
2. Lantzsch, R.; Arlt, D. Synthesis 1977, 756–757.
(
1.471 g) was treated with boiling MeCN (25 mL), and the resulting hot
3. Zigeuner, G.; Fuchsgruber, A.; Wede, F. Monatsh. Chem. 1975, 106, 1495–1497.
4. Kobayashi, M.; Tanaka, J.; Katori, T.; Marsuura, M.; Yamashita, M.; Kitagawa, I.
Chem. Pharm. Bull. 1990, 38, 2409–2418.
solution was filtered through a paper filter (for coarse deposits) to remove the
insoluble pink oil, and concentrated in vacuo. The residue was triturated with
Et
was filtered, washed with Et
semicarbazide 14a (1.231 g, 60%, slightly pink solid) as a mixture of (E)- and
2
O (10 mL), the resulting suspension was cooled (À18 °C). The precipitate
1
1
5. (a) Lu, X.; Deng, L. Angew. Chem., Int. Ed. 2008, 47, 7710–7713; (b) Xu, L.-W.;
Xia, C.-G. Synthesis 2004, 2191–2195; (c) Kobayashi, S.; Kakumoto, K.; Sugiura,
M. Org. Lett. 2002, 4, 1319–1322.
6. (a) Wang, R.; Huang, T.; Shi, L.; Li, B.; Lu, X. Synlett 2007, 2197–2200; (b) Xu, L.-
W.; Wang, Z.-T.; Xia, C.-G.; Li, L.; Zhao, P.-Q. Helv. Chim. Acta 2004, 87, 2608–
2
O
and petroleum ether, and dried to give
(Z)-isomers in a ratio of 84:16. An analytically pure sample as a white solid
(
isomeric ratio 85:15) was obtained after two crystallizations from MeCN. Mp
1
30–134 °C (dec, MeCN). Anal. Calcd for C11
Found: C, 56.31; H, 7.32; N, 29.64.
Synthesis of the hydrazone
yl}semicarbazide (14b): A solution of compound 12b (2.240 g, 8.98 mmol) in
(23 mL) was refluxed under stirring for 24 h. At the beginning of reflux,
the mixture was flushed with Ar. A drying tube containing KOH was used to
protect the reaction mixture from air moisture and CO . After completion of
the reaction, N was removed in vacuo (the temperature of the bath was
about 60 °C) until a white oily residue remained, which was co-evaporated
with toluene (4 Â 10 mL). The obtained solid was suspended in Et O (15 mL)
and cooled (À18 °C). The precipitate was filtered, washed with Et O, and dried
to give semicarbazide 14b (1.447 g, 65%, white solid) as a mixture of (E)- and
Z)-isomers in a ratio of 90:10. An analytically pure sample (0.140 g, a 96:4
mixture of isomers) was obtained from crude 14b (0.511 g) after two
17 5
H N O: C, 56.15; H, 7.28; N, 29.77.
2
612; (c) Ten Hoeve, W.; Wynberg, H. Synth. Commun. 1994, 24, 899–906.
1
1
7. (a) Tillman, A. L.; Ye, J.; Dixon, D. J. Chem. Commun. 2006, 1191–1193; (b)
Kanazawa, A. M.; Denis, J.-N.; Greene, A. E. J. Org. Chem. 1994, 59, 1238–1240.
8. (a) Shutalev, A. D.; Kurochkin, N. N. Mendeleev Commun. 2005, 15, 70–72; (b)
Sivova, N. V.; Shutalev, A. D. Chem. Heterocycl. Compd. 1995, 31, 246–247.
9. Engberts, J. B. F. N.; Strating, J. Recl. Trav. Chim. 1965, 84, 942–950.
of
3-{[1-(4-methylphenyl)-3-oxo]but-1-
2 4
N H
1
2
2
0. Synthesis of ethyl N-[(phenyl)(tosyl)methyl]carbamate (7a): To
emulsion of benzaldehyde (5.660 g, 53.34 mmol) in H O (25 mL) were added
p-toluenesulfinic acid (8) (8.342 g, 53.40 mmol) and H O (25 mL) and the
resulting mixture was stirred for 20 min at room temperature. To the formed
suspension were added ethyl carbamate (9) (4.767 g, 53.51 mmol) and H
16 mL) and the suspension was heated under stirring in a water bath (70 °C).
a stirred
2 4
H
2
2
2
2
2
O
(
(
After 5 min, an oily material formed and after 25 min it started to solidify.
Heating of the reaction mixture (70 °C, water bath) was continued for 1 h in

A. D. Shutalev et al. / Tetrahedron Letters 55 (2014) 5481–5485
5485
crystallizations from MeCN followed by washing of the obtained solid (0.293 g)
with distilled H
O (8 Â 2 mL), and drying. Mp 145–146.5 °C (dec, MeCN). Anal.
Calcd for C12 O: C, 57.81; H, 7.68; N, 28.09. Found: C, 57.81; H, 7.69; N, 27.81.
4. Synthesis of 7,14-dimethyl-5,12-diphenyl-1,2,4,8,9,11-hexaazacyclotetradeca-
,14-diene-3,10-dione (19a): To semicarbazide 14a (0.875 g, 3.72 mmol) were
O (0.850 g, 4.47 mmol) and EtOH (30 mL) and the obtained
Synthesis of 7,14-dimethyl-5,12-di(4-methylphenyl)-1,2,4,8,9,11-hexaazacyclo-
tetradeca-7,14-diene-3,10-dione (19b): Compound 19b (0.564 g, 80%, white
solid) was prepared from crude semicarbazide 14b (0.810 g, 3.25 mmol) and
2
19 5
H N
2
TsOHÁH
2
O (0.745 g, 3.92 mmol) in EtOH (25 mL) (reflux, 4 h) as described for
À1
7
19a. Mp 315 °C (dec, AcOH). IR (Nujol)
3027 (w) (
1518 (sh) (
m
, cm : 3366 (s), 3190 (s), 3084 (s),
added TsOHÁH
2
m
NH), 1674 (vs), 1636 (m) (amide-I), 1544 (vs) (
m C@N, amide-II),
+
mixture was refluxed for 4 h under stirring. At the beginning of the reaction the
solid dissolved and a new precipitate appeared immediately. After completion
of the reaction, the solvent was removed in vacuum. The solid residue was
m CCarom), 808 (s) (d CHarom). MS (EI) m/z 435 [4, (M+1) ], 434 (15,
+
M ), 320 (3), 277 (1), 258 (3), 218 (9), 217 (26), 201 (9), 173 (7), 158 (5), 146
(44), 120 (100), 118 (20), 91 (24), 44 (7), 42 (9), 41 (10). Anal. Calcd for
triturated with saturated aqueous NaHCO
The obtained suspension was cooled (0 °C) and the precipitate filtered, washed
with ice-cold H O and petroleum ether, and dried to give bis-semicarbazone
9a (0.517 g, 68%, white solid) as single diastereomer. When crystallized
semicarbazide 14a was used the yield of compound 19a was 71%. Mp 273 °C
3
(6 mL) and petroleum ether (5 mL).
24 30 6 2
C H N O : C, 66.34; H, 6.96; N, 19.34. Found: C, 66.10; H, 6.88; N, 19.46.
25. Crystallographic data for the structural analyses of macrocycles 19a and 19b
have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication Nos. CCDC 928685 and 1003952, respectively.
Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
2
1
(
dec, DMF). 1H NMR (300.13 MHz, DMSO-d
) d: 9.42 (2H, s, NHN), 7.91 (2H, d,
6
3
3
3
2
J = 7.6 Hz, NHC), 7.20–7.37 (10H, m, ArH), 5.02 (2H, ddd, J = 7.6, 3J = 5.1,
2
3
J = 4.2 Hz, CHN), 2.69 (2H, dd, J = 14.0, J = 4.2 Hz, H
A
in CH
2
), 2.66 (2H, dd,
26. To our knowledge, this class of azamacrocycles is unknown. However, their
J = 14.0, 3J = 5.1 Hz, H
13
28
B
in CH
2 3
), 1.49 (6H, s, CH ). C NMR (75.48 MHz, DMSO-
more unsaturated analogs have been described in the literature.
d
1
3
1
6
2
6
) d: 155.33 (2C@O), 148.78 (2C@N), 142.74 (2C), 128.22 (4CH), 126.65 (2CH),
27. This compound was described as an oil in Ref. 29.
À1
25.71 (4CH), 51.12 (2CHN), 43.33 (2CH
371 (s), 3197 (s), 3087 (s), 3032 (m) (
584 (w) ( CCarom), 1550 (vs) ( C@N, amide-II), 1495 (m) (m
+
2
), 19.11 (2CH
3
). IR (Nujol)
m
, cm
:
28. (a) Chandra, S.; Gautam, A. J. Serb. Chem. Soc. 2009, 74, 1413–1422; (b)
Gradinaru, J. I.; Simonov, Y. A.; Arion, V. B.; Bourosh, P. N.; Popovici, M. A.;
Bel’skii, V. K.; Gerbeleu, N. V. Inorg. Chim. Acta 2001, 313, 30–36; (c) Vlasiuk, S.
V.; Pavlovsky, V. I.; Andronatti, S. A.; Gdaniec, M.; Simonov, Y. A. Chem.
Heterocycl. Compd. 2000, 36, 1077–1085.
m
NH), 1674 (vs), 1638 (w) (amide-I),
CCarom), 756 (s),
m
m
+
96 (s) (d CHarom). MS (EI) m/z 407 [5, (M+1) ], 406 (21, M ), 335 (1), 301 (1),
92 (7), 244 (8), 204 (13), 203 (29), 187 (10), 159 (6), 144 (3), 132 (24), 106
(
100), 104 (17), 91 (8), 77 (16), 44 (12). Anal. Calcd for C22
H
26
N
6
O
2
: C, 65.01; H,
29. Yang, B.-L.; Weng, Z.-T.; Yang, S.-J.; Tian, S.-K. Chem. Eur. J. 2010, 16, 718–723.
6
.45; N, 20.68. Found: C, 64.99; H, 6.53; N, 20.77.