Different modes of acid-catalyzed cyclization of 4-(γ-oxoalkyl)semicarbazide hydrazones: 7-membered versus 14-membered cyclic semicarbazones formation

Article abstract of DOI:10.1016/j.tet.2015.10.079

Acid-catalyzed cyclization of 4-(γ-oxoalkyl)semicarbazide hydrazones has been studied. 7-Membered cyclic semicarbazones, 2,4,5,6-tetrahydro-3H-1,2,4-triazepin-3-ones, were obtained from the γ-phenyl-substituted semicarbazides, while the cyclization of the γ-methyl-substituted semicarbazides involved two molecules of the starting material to result in 14-membered cyclic bis-semicarbazones, 1,2,4,8,9,11-hexaazacyclotetradeca-7,14-diene-3,10-diones. The 4-(γ-oxoalkyl)semicarbazide hydrazones were prepared according to a four-step synthesis based on amidoalkylation of the sodium enolates of 1,3-diketones with ethyl N-(1-tosylalk-1-yl)carbamates followed by base-promoted retro-Claisen reaction and treatment of the obtained ethyl N-(γ-oxoalkyl)carbamates with hydrazine.

Full text of DOI:10.1016/j.tet.2015.10.079

Tetrahedron 71 (2015) 9528e9543
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Different modes of acid-catalyzed cyclization of 4-(g-oxoalkyl)
semicarbazide hydrazones: 7-membered versus 14-membered
cyclic semicarbazones formation
*
Anastasia A. Fesenko, Anatoly D. Shutalev
Department of Organic Chemistry, Moscow State University of Fine Chemical Technologies, 86 Vernadsky Avenue, 119571 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 August 2015
Received in revised form 14 October 2015
Accepted 27 October 2015
Available online 30 October 2015
Acid-catalyzed cyclization of 4-(
cyclic semicarbazones, 2,4,5,6-tetrahydro-3H-1,2,4-triazepin-3-ones, were obtained from the
substituted semicarbazides, while the cyclization of the
g
-oxoalkyl)semicarbazide hydrazones has been studied. 7-Membered
-phenyl-
-methyl-substituted semicarbazides involved
two molecules of the starting material to result in 14-membered cyclic bis-semicarbazones, 1,2,4,8,9,11-
hexaazacyclotetradeca-7,14-diene-3,10-diones. The 4-( -oxoalkyl)semicarbazide hydrazones were pre-
g
g
g
pared according to a four-step synthesis based on amidoalkylation of the sodium enolates of 1,3-
diketones with ethyl N-(1-tosylalk-1-yl)carbamates followed by base-promoted retro-Claisen reaction
Keywords:
Amidoalkylation
Retro-Claisen reaction
Semicarbazides
and treatment of the obtained ethyl N-(
g
-oxoalkyl)carbamates with hydrazine.
Ó 2015 Elsevier Ltd. All rights reserved.
Heterocyclic semicarbazones
1,2,4-Triazepin-3-ones
Azamacrocycles
1. Introduction
Five- and six-membered cyclic semicarbazones, 2,4-dihydro-
3H-1,2,4-triazol-3-ones 1 and 2,3,4,5-tetrahydro-1,2,4-triazin-3-
ones 2 are readily available and well-studied heterocycles1,2 pos-
sessing a wide range of biological activities.3e10 In contrast to 1 and
2, no general approaches to their seven-membered analogs, 2,4,5,6-
tetrahydro-3H-1,2,4-triazepin-3-ones 3, or cyclic semicarbazones
with larger ring sizes have been described. Several compounds of
type 3 have been prepared by the reaction of 4-isocyanato-4-
methylpentan-2-one with methylhydrazine,11 oxidation of 5,5,7-
Scheme 1. Retrosynthesis of 2,4,5,6-tetrahydro-3H-1,2,4-triazepin-3-ones 5.
Published data show that, compounds 7 can be synthesized by
aza-Michael addition of carbamates to a,b
-unsaturated ketones,15
trimethyl-2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thione,12
or
cyclizations of two semicarbazones.13 Thus, the development of
a convenient and general synthesis of triazepinones 3 is of signif-
icant synthetic and medicinal value.
Mannich condensation of aldehydes with methyl ketones and car-
bamates,16 reactions of N-alkoxycarbonylimines with ketones,17 etc.
Small-scale preparation and use of chromatography for isolation of
the target products are the main drawbacks of the reported syn-
theses.18 We supposed that compounds 7 could be prepared on
a multi-gram scale by retro-Claisen reaction of carbamates 8, which
are readily available using our previously described protocol based
on amidoalkylation reactions.19
In continuation of our studies on the application of ami-
doalkylation in heterocyclic synthesis,14 we were interested to use
this method for the preparation of seven-membered cyclic semi-
carbazones 3, particularly their 2-unsubstituted representatives 5.
We hypothesized that the latter could form via cyclization of 4-(g-
According to the synthetic sequence described above we have
oxoalkyl)semicarbazides 6 prepared by reaction of
ketones 7 with hydrazine (Scheme 1).
b-carbamato
prepared two ethyl N-(2-acetyl-3-oxobut-1-yl)carbamates
8
(R2¼Me) in two steps.20 Compounds 8 were converted into the
corresponding carbamates 7 under the action of aqueous KOH
followed by treatment with hydrazine to give hydrazones of sem-
icarbazides 9. Surprisingly, acid-catalyzed cyclization of hydrazones
* Corresponding author. Tel.: þ7 495 936 8908; fax: þ7 495 936 8909; e-mail
addresses: anatshu@gmail.com, shutalev@orc.ru (A.D. Shutalev).
http://dx.doi.org/10.1016/j.tet.2015.10.079
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

A.A. Fesenko, A.D. Shutalev / Tetrahedron 71 (2015) 9528e9543
9529
Table 1
9 involved two molecules of the starting material and stereo-
selectively afforded previously unknown 14-membered cyclic bis-
semicarbazones 10 instead of the expected triazepinones 11
(Scheme 2).20
Reaction of aldehydes 14aef with ethyl carbamate (12) and p-toluenesulfinic acid
(13) in water
Entry
14
R
Reaction conditionsa
Product
Yield (%)b
1
2
3
4
5
6
14a
14b
14c
14d
14e
14f
Ph
70 ꢀC, 1 h
70 ꢀC, 1.5 h
rt, 24 h
rt, 24 h
70 ꢀC, 1.5 h
70 ꢀC, 1.5 h
15a
15b
15c
15d
15e
15f
88
86
92
81
93
94
4-MeC6H4
4-MeOC6H4
4-t-BuC6H4
4-ClC6H4
Pr
a
Temperature in a water bath (entries 1, 2, 5, and 6).
Isolated yields (>95% purity).
b
Scheme 2. Acid-catalyzed cyclization of semicarbazides 9 into 14-membered cyclic
bis-semicarbazones 10.
Under optimized conditions sulfones 15aef precipitated from
the reaction mixtures formed after the addition of all reagents.
They were isolated as white solids by filtration with >95% purity
according to 1H NMR spectroscopic data of the crude products and
used in the amidoalkylation step without additional purification.
The nucleophilic substitution of the tosyl group in sulfones
15aef under the action of sodium enolates of acetylacetone (16a),
3-methylpentane-2,4-dione (16b), or dibenzoylmethane (16c),
generated by the treatment of the corresponding CH-acid with NaH
in dry MeCN or THF, readily proceeded at room temperature to give
carbamates 17aeo in high yields (Scheme 4).
We focused our further attention on the elucidation of the fac-
tors that determine the course of the acid-catalyzed cyclization of
hydrazones of 4-(g-oxoalkyl)semicarbazides, particularly on the
effect of substituents and the reaction conditions, to develop gen-
eral approaches to both 7-membered and 14-membered cyclic
semicarbazones. Here we report the three-step multi-gram syn-
thesis of ethyl carbamates 7 bearing various R2, R3, and R4 groups
involving the preparation of carbamates 8 followed by retro-Claisen
reaction, and the transformation of compounds 7 under the action
of hydrazine to provide the hydrazones of semicarbazides 6. The
acid-catalyzed cyclization of the obtained hydrazones affording
2,4,5,6-tetrahydro-3H-1,2,4-triazepin-3-ones
or
1,2,4,8,9,11-
hexaazacyclotetradeca-7,14-diene-3,10-diones depending on the
structure of the starting material is described.
2. Results and discussion
Scheme 4. Synthesis of ethyl N-[(b-acyl-g-oxo)alkyl]carbamates 17aeo.
2.1. Synthesis of ethyl N-[(b-acyl-g-oxo)alkyl]carbamates
The reaction conditions and yields of the prepared ethyl N-[(
b-
acyl- -oxo)alkyl]carbamates 17aeo are summarized in Table 2.
g
For preparation of the starting amidoalkylation reagents, ethyl
N-(1-tosylalk-1-yl)carbamates 15, we applied a modified Engberts
method based on condensation of carbamates with aldehydes and
arylsulfinic acids generated by treatment of their sodium salts with
excess formic acid.21 The modification involved the use of pure
sulfinic acids instead of their in situ formation. Our experience has
shown that both yield and purity of products formed under these
conditions are satisfactory.19 Thus, carbamates 15aef were ob-
tained by the three-component condensation of ethyl carbamate
(12) (1e1.21 equiv) with p-toluenesulfinic acid (13) (1 equiv) and
aldehydes 14aef (1 equiv) in water (Scheme 3).
The Na-enolate of acetylacetone (16a) was readily formed in dry
MeCN and smoothly reacted with sulfones 15aed,f to afford car-
bamates 17aee (entries 1e5). In contrast to 16a, deprotonation of
16c with NaH in MeCN proceeded with the formation of a dense
suspension which complicated the completion of the reaction. The
rate of deprotonation of 16b under these conditions was very slow.
Therefore, dry THF was used as solvent for generation of the Na-
enolates of 16b,c followed by their reaction with sulfones 15aef
(entries 6e15).
Table 2
Reaction of sulfones 15aef with 1,3-diketones 16aec in the presence of NaH at room
temperaturea
Entry 15 16
R
R1 R2 Solvent Reaction Product Isolated
time (h)
yield (%)
1
2
3
4
5
6
7
8
15a 16a Ph
H
H
H
H
H
Me MeCN
8
17a
17b
17c
17d
17e
17f
17g
17h
17i
17j
17k
17l
17m
17n
17o
93
91
90
93
89
81
87
83
84
95
96
93
98
98
95
15b 16a 4-MeC6H4
15c 16a 4-MeOC6H4
15d 16a 4-t-BuC6H4
15f 16a Pr
Me MeCN 9.5
Me MeCN 8.67
Me MeCN 8.17
Me MeCN 8.17
Scheme 3. Synthesis of ethyl N-(1-tosylalk-1-yl)carbamates 15aef.
15a 16b Ph
Me Me THF
8.08
8.17
8.08
8.33
8
8
8
8
8
Table 1 shows the optimized reaction conditions for this re-
action and yields of sulfones 15aef. The condensation of ethyl
carbamate (12) with aldehydes 14a,b,e,f and sulfinic acid 13 pro-
ceeded in water at 70 ꢀC for 1e1.5 h to give the corresponding
sulfones 15a,b,e,f in 86e94% yields. For aldehydes 14c,d, the best
result was achieved when the condensation proceeded at room
temperature for 24 h to afford sulfones 15c,d in 92 and 81% yields,
respectively. Heating of the reaction mixtures in this case (70 ꢀC,
1.5 h) led to a significant decrease in both yield and purity of iso-
lated products 15c,d.
15b 16b 4-MeC6H4 Me Me THF
15c 16b 4-MeOC6H4 Me Me THF
15d 16b 4-t-BuC6H4 Me Me THF
9
10
11
12
13
14
15
15a 16c Ph
H
H
H
H
H
H
Ph THF
Ph THF
Ph THF
Ph THF
Ph THF
Ph THF
15b 16c 4-MeC6H4
15c 16c 4-MeOC6H4
15d 16c 4-t-BuC6H4
15e 16c 4-ClC6H4
15f 16c Pr
8
a
15/16/NaH molar ratios: 1:1.11:1.10 (entry 1), 1:1.02:1.01 (entry 2),
1:(1.02e1.04):1 (entries 3e5), 1:(1.00e1.01):1 (entries 5e9), and 1:(1.03e1.05):1
(entries 10e15).

9530
A.A. Fesenko, A.D. Shutalev / Tetrahedron 71 (2015) 9528e9543
2.2. Synthesis of ethyl N-(
g
-oxoalkyl)carbamates
2.3. Synthesis of hydrazones of 4-(g-oxoalkyl)semicarbazides
According to the retrosynthetic analysis (Scheme 1), the next
step of cyclic semicarbazone synthesis included removal of one of
two geminal acyl groups from ethyl N-[(b-acyl-g-oxo)alkyl]carba-
mates 17 using the retro-Claisen reaction. This transformation
proceeded under treatment of 17 with KOH in water or aqueous
Next, ethyl N-( -oxoalkyl)carbamates 18 were reacted with
g
hydrazine. Previously, we studied the reaction of carbamate 18a
with hydrazine under various conditions using 1H NMR spectros-
copy.22 We found that this reaction proceeded in two sequential
steps involving a relatively fast formation of hydrazone 19a fol-
lowed by slow substitution of the ethoxy group resulting in the
target hydrazone of semicarbazide 20a (Scheme 6).
EtOH at room temperature to give the corresponding N-(
oxoalkyl)carbamates 18aei (Scheme 5).
g-
Scheme 5. Synthesis of ethyl N-(g-oxoalkyl)carbamates 18aei.
Table 3 shows the optimized reaction conditions for the prep-
aration of N-( -oxoalkyl)carbamates 18aei from 17aed,h,j,k,l,n by
g
the retro-Claisen reaction.
Ethyl N-(3-oxobutyl)carbamates 18aes were prepared in high
isolated yields by treatment of compounds 17aes with aqueous
solutions of KOH (5.06e5.12 equiv) at room temperature for 3 h
(entries 1e3). Ethyl N-(2-methyl-3-oxobutyl)carbamate 17h un-
derwent the retro-Claisen reaction under the described conditions
over 1 h 50 min to give compound 18e in 74% yield as a mixture of
two isomers (entry 5). With longer reaction time the yield of
compound 17h significantly decreased. The conditions of retro-
Claisen reaction for carbamates prepared from dibenzoylmethane
were optimized using compound 17j as a starting material. With
aqueous KOH (5.00 equiv) the reaction did not proceed due to the
low solubility of carbamate 17j in H2O. Therefore, EtOH was added
as a co-solvent and 17j was reacted with KOH (4.87 equiv) at room
temperature for 8 h 45 min. After extractive workup of the resulting
reaction mixture the 1H NMR spectrum of the obtained material
showed the complete conversion of starting compound but sig-
nificant amounts of side products (up to 60%) formed along with
carbamate 18f. When the reaction time was reduced to 3 h and the
amount of KOH to 2.99 equiv, a 17:83 mixture of starting 17j and
product 18f was obtained. Under these conditions the formation of
side products was not observed. Thus, 3-phenyl substituted car-
bamate 18f was isolated in 69% yield by the reaction of 17j with
KOH (3.01 equiv) in aqueous EtOH at room temperature for 8 h
(entry 6). Under the described conditions carbamates 18gei were
prepared in 66e83% yields (entries 7e9). Carbamates 18aec,eei
were isolated with >95% purity (1H NMR data) by the filtration of
the precipitate formed in the reaction mixture. Only compound 18d
(oily substance) was isolated using an extractive workup. Thus,
Scheme 6. Synthesis of the hydrazones of 4-(g-oxoalkyl)semicarbazides 20aeh.
The reaction of 18a with hydrazine hydrate or anhydrous hy-
drazine in different solvents (EtOH, n-BuOH, Py) at room temper-
ature or at reflux gave mixtures of hydrazone 19a and azine 22. The
substitution of the ethoxy group by a hydrazino group did not
proceed under these conditions. In contrast, in refluxing anhydrous
hydrazine or hydrazine hydrate, gradual transformation of the in-
termediate hydrazone 19a into semicarbazide 20a (a mixture of E-
and Z-isomers) was practically complete in 24 h and formation of
azine 22 was completely suppressed. Dihydropyrazole 23 resulting
from elimination of semicarbazide in 20a followed by ring closure
was the major by-product (up to 61%) formed in the reaction with
hydrazine hydrate. According to 1H NMR data, the best results were
achieved in refluxing anhydrous hydrazine for 20e24 h20 In this
case, compound 20a was isolated in a 36% yield after evaporation of
the reaction mixture in vacuo to dryness followed by washing of the
residue with Et2O and water (Table 4, entry 1).
Similar trends were observed for the reaction of other N-(g-
oxoalkyl)carbamates 18beh with hydrazine under the above de-
scribed conditions: the first step involved a fast formation of
hydrazones of carbamates 19beh followed by their slow conver-
sion to hydrazones of semicarbazides 20beh (Scheme 6). Forma-
tion of variable amounts of the corresponding azines and
dihydropyrazoles similar to 22 and 23 was also observed. As for 18a,
reaction of 18beh in refluxing anhydrous hydrazine for 20e24 h
a simple and convenient method for the preparation of ethyl N-(g-
oxoalkyl)carbamates in a multi-gram scale was developed.18
Table 3
Transformation of 17aed,h,j,k,l,n into ethyl N-(g-oxoalkyl)carbamates 18aei in the presence of KOH
Entry
17
R
R1
R2
KOH (equiv)
Solvent
Reaction time
Product
Isolated yield (%)
1
2
3
4
5
6
7
8
9
17a
17b
17c
17d
17h
17j
17k
17n
17l
Ph
H
H
H
H
Me
H
H
H
H
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
5.06
5.12
5.12
5.17
3.00
3.01
3.00
3.31
2.98
H2O
H2O
H2O
H2O
3 h
3 h
3 h
4 h
1 h 50 min
8 h
9 h 20 min
8 h
18a
18b
18c
18d
18e
18f
18g
18h
18i
83
91
92
da
74b
69
67
83
66
4-MeC6H4
4-MeOC6H4
4-t-BuC6H4
4-MeOC6H4
Ph
4-MeC6H4
4-ClC6H4
4-MeOC6H4
H2O
H2OeEtOH (5:3)
H2OeEtOH (5:3)
H2OeEtOH (5:3)
H2OeEtOH (17:9)
9 h
a
After extractive workup followed by removal of solvent compound 18d was isolated as an oil (93% purity) and used in the next step.
A mixture of two diastereomers, 51:49.
b

A.A. Fesenko, A.D. Shutalev / Tetrahedron 71 (2015) 9528e9543
9531
protons and between the C]NNH2 and CHN protons, thus giving
evidence for the E-configuration of the C]N double bond in this
isomer. As for the minor isomer of compound 20h, these correla-
tions were not detected. Comparison of 1H and 13C NMR spectra of
20h and 20f,g allowed us to conclude that the major isomers of
20f,g had the same E-configuration.
It is important to note that the relative configurations of the
major stereoisomers of 20aee and 20feh were different, namely,
the CH3 and NH2 groups of 20aee had cis-orientation with respect
to the C]N bond, and the Ph and NH2 groups of 20feh were in the
trans-position.
Table 4
Reaction of ethyl N-(
reflux
g
-oxoalkyl)carbamates 18aeh with anhydrous hydrazine at
Entry 18
R
R1 R2 Reaction Product E/Z isomer Isolated
time (h)
Me 23
Me 20
Me 24
Me 22
ratio
yield (%)
1
2
3
4
5
6
7
8
18a Ph
H
H
H
H
20a
20b
20c
20d
20e
20f
84:16
90:10
92:8
94:6
95:5
75:25
84:16
75:25
36
41
29
42a
40
46
28
32
18b 4-MeC6H4
18c 4-MeOC6H4
18d 4-t-BuC6H4
18e 4-MeOC6H4 Me Me 23
18f Ph
H
H
H
Ph 19.66
Ph 24
Ph 20
18g 4-MeC6H4
18h 4-ClC6H4
20g
20h
2.4. Acid-catalyzed cyclizations of 4-(g-oxoalkyl)semi-
a
Counting on carbamate 17d.
carbazide hydrazones
Finally, we studied heterocyclization of hydrazones of 3-
oxobutyl- 20aee and (3-oxo-3-phenyl)propyl-substituted semi-
carbazides 20feh under acidic conditions.
Previously, we found that reflux of semicarbazides 20a,b in
EtOH or MeCN for 4 h in the presence of TsOH (1.2 equiv) gave 14-
membered cyclic bis-semicarbazones instead of the expected 1,2,4-
triazepin-3-ones (see Scheme 2).20 In continuation of this research
we studied acid-catalyzed cyclization of 20a,b and their close an-
alogues 20cee into hexaazamacrocycles 24aee in more details
(Scheme 7, Table 5).
gave the best results. Though the conversion of 18aeh into 20aeh
proceeded under drastic conditions and was accompanied by some
side reactions, the impurities were completely removed from the
crude products during isolation. After evaporation of all the vola-
tiles and treatment of the residues with diethyl ether, the resulting
solids were filtered, washed with ether to remove all side products,
and then with ice-cold H2O to remove the residual hydrazine. All
compounds 20aeh are poorly soluble in ether and ice-cold H2O.
Table 5 shows the optimized reaction times, yields and E/Z-isomer
ratios of all prepared hydrazones of semicarbazides 20aeh.
The crude semicarbazides 20aeh were isolated as mixtures of E-
and Z-isomers with significant predominance of one of them (up to
95%) (Table 4). Configurations of the major and minor isomers of
compound 20a were determined unambiguously using a 1H,1H-
NOESY experiment in DMSO-d6. For the major isomer NOE was
observed between the CH3 and C]NNH2 protons, thus indicating
the E-configuration of the C]N double bond in this isomer. The
stereochemical assignments for 20a were confirmed by comparison
of the experimental carbon chemical shifts for the CH2 and CH3
groups of the CH2C(¼NNH2)CH3 moiety with those calculated by
the GIAO method at the RHF/6-311þG(2d,p) level using the DFT-
B3LYP/6-31þG(d,p) optimized geometries for both E-20a and Z-
20a.23 The DFT calculations at the B3LYP/6-31þG(d,p) level also
showed that the E-isomer of 20a was more stable (1.91 kcal/mol in
DMSO) than the Z-isomer. Since the 1H and 13C NMR spectra of the
major isomers of 20a and 20bee were similar, we concluded that
the major isomers of 20bee also had the E-configuration.
Scheme 7. Synthesis of 1,2,4,8,9,11-hexaazacyclotetradeca-7,14-diene-3,10-diones
24aee.
We found that TsOH was an effective acid promoter for the
synthesis of 24aee. The optimal amount of TsOH was shown to be
1.03e1.07 equiv. With 2.05 equiv of TsOH (entry 5), the yield and
purity of isolated macrocycle 24a significantly decreased, while the
trans/cis diastereoselectivity of the reaction changed only slightly
(entry 1 vs entry 5). Relatively weak AcOH also induced the cycli-
zation of semicarbazide 20b in refluxing EtOH (entry 9). Both in the
case of AcOH (entry 9) and with the use of 2.05 equiv of TsOH (entry
5), the 1H NMR spectra of isolated crude 24a,b showed some un-
identified side products. A change of solvent from EtOH to MeCN
had no effect on the yield and diastereoselectivity of the formation
of macrocycle 24a (entry 1 vs entry 2).
A
1H,1H-NOESY experiment in DMSO-d6 was used to assign
stereochemistry of the isomers of compound 20h. For the major
isomer, NOEs were observed between the C]NNH2 and CH2
Table 5
Acid-catalyzed transformation of hydrazones of 4-(3-oxobut-1-yl)semicarbazides 20aee into 1,2,4,8,9,11-hexaazacyclotetradeca-7,14-diene-3,10-diones 24aee
Entry
20
R
R1
Conc. of 20 (mol/L)
Acid (equiv)
Solvent
Reaction conditions
Product
Yield (%)a
Drc
1
2
3
4
5
6
7
8
20a
20a
20a
20a
20a
20b
20b
20b
20b
20c
20d
20d
20e
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
Me
0.191
0.172
0.060
0.177
0.182
0.203
0.062
0.183
0.156
0.200
0.165
0.076
0.270
TsOH (1.03)
TsOH (1.05)
TsOH (1.06)
TsOH (1.05)
TsOH (2.05)
TsOH (1.05)
TsOH (1.05)
TsOH (1.04)
AcOH (1.27)
TsOH (1.06)
TsOH (1.06)
TsOH (1.07)
TsOH (1.04)
EtOH
MeCN
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Reflux, 1 h 50 min
Reflux, 1 h 50 min
Reflux, 1 h 50 min
rt, 4 h
Reflux, 1 h 50 min
Reflux, 1 h 50 min
Reflux, 1 h 50 min
rt, 4 h
24a
24a
24a
24a
24a
24b
24b
24b
24b
24c
24d
24d
24e
85
85
76
80
db
92
83
82
db
86
90
93
73
95:5
96:4
82:18
57:43
98:2
71:29
26:74
23:77
32:68
69:31
65:35
55:45
81:13:6
Ph
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-t-BuC6H4
4-t-BuC6H4
4-MeOC6H4
9
Reflux, 2 h
10
11
12
13
Reflux, 1 h 50 min
Reflux, 1 h 50 min
Reflux, 1 h 50 min
Reflux, 1 h 50 min
a
Isolated yields (>96% purity).
b
c
Some unidentified side products were formed.
Diastereomeric ratio (trans/cis for 20aed). According to 1H NMR spectroscopic data for the crude products.

9532
A.A. Fesenko, A.D. Shutalev / Tetrahedron 71 (2015) 9528e9543
Decrease in concentration led to a slight decrease in the yield of
Thus, 4-(3-oxobutyl)semicarbazides 20aee under acidic condi-
tions afford cyclic bis-semicarbazones 24aee, but not the corre-
sponding 1,2,4-triazepin-3-ones. We suppose that the formation of
the latters is completely suppressed, since the major isomers
(84e95%, Table 4) of 20aee have E-configuration, which is un-
favorable for cyclization into 7-membered cyclic semicarbazones.
In contrast to 20aee, TsOH-catalyzed cyclization of hydrazones
24a (entry 1 vs entry 3) and 24b (entry 6 vs entry 7) and had no
effect on the yield of 24d (entry 11 vs entry 12). In relatively diluted
solutions the stereoselectivity of formation of macrocycles 24a and
24d decreased (entry 1 vs entry 3; entry 11 vs entry 12), but in the
case of 24b, the reversed selectivity was observed (entry 6 vs entry
7).
Transformation of semicarbazides 20a,b into macrocycles 24a,b
smoothly proceeded at room temperature under the action of TsOH
(entries 4, 8). For both compounds the yields slightly decreased
compared with those achieved in refluxing solvents. The obtained
data clearly demonstrated that the reaction temperature had
a dramatic effect on the diastereoselectivity of the reaction (entry 1
vs entry 4; entry 6 vs entry 8).
of g-phenyl substituted semicarbazides 20feh resulted in forma-
tion of triazepines 29aec (Scheme 9). No corresponding macrocy-
clic bis-semicarbazones were detected in the crude isolated
materials (1H NMR data).
Under similar conditions, the reaction stereoselectivity also
decreased with increasing steric bulk of the substituent at the 4-
position of the aromatic ring (from H to t-Bu; entries 1, 6, 10, and
11). As expected, in the case of 24e possessing four stereocenters,
the number of the formed diastereomers increased, but one of
them significantly predominated (entry 13).
Scheme 9. Synthesis of 2,4,5,6-tetrahydro-3H-1,2,4-triazepin-3-ones 29aec.
Compounds 24aee were formed as white solids which were
extremely poorly soluble (especially 24b) in common solvents in-
cluding DMSO, DMF, etc. Their structures were established by IR, 1H
and 13C NMR spectroscopy, mass spectrometry, and powder X-ray
diffraction24 (for 24a,b). According to NMR spectral data and X-ray
analysis, the major diastereomer of 24aed had a trans-orientation
of the aryl groups.
The reaction conditions for the transformation of 20feh into
29aec were optimized using semicarbazide 20f as a starting ma-
terial (Table 6).
First of all, we found that more than 1 equiv of TsOH was re-
quired for the complete conversion of the starting material, oth-
erwise the reaction did not proceed (entries 1, 2). Under all studied
conditions some amount of unidentified side products always
formed along with triazepinone 29a according to 1H NMR spec-
troscopic data for the isolated crude materials. The characteristic
features of these spectra were an increase in the relative integral
intensity of the aromatic protons region (6.6e8.2 ppm), the un-
resolved very broad signals at 2.8e3.6, 4.8e5.3, and 9.7e10.5 ppm.
The amount of these side products depended on the starting con-
centration of 20f. At higher concentrations, the amount of side
products increased (entries 5, 6, and 7). Solvent polarity had little
effect on the product formation (entries 3e5). The reaction tem-
perature caused dramatic changes (entries 3e7 vs entry 8). At room
temperature triazepinone 29a was formed in insignificant amounts
(1H NMR data). Triazepinones 29aec were very soluble in common
solvents and were isolated using column chromatography on silica
gel in moderate yields (entries 7, 9, and 10).
Since macrocycles 24aed have two distant stereocenters, we
expected them to form as mixtures of two diastereomers in ap-
proximately equal amounts. However, as mentioned above, the
stereoselectivity varied in a wide range and strongly depended on
the reaction conditions and the structure of the starting material
(Table 5). Thus, the formation of 24aed via intermediates 25aed
could be excluded (Scheme 8). We suppose that immediate pre-
cursors to 24aed possess only one stereogenic center, and forma-
tion of the second stereocenter proceeds during the cyclization. A
plausible pathway for the transformation of 20aee into 24aee
presumably could include acid-catalyzed elimination of semi-
carbazide resulting in unsaturated hydrazones 26aee followed by
the formation of semicarbazones 27aee. Dimerization of com-
pounds 27aee via intermolecular aza-Michael addition affords in-
termediates 28aee which cyclize through an intramolecular aza-
Michael reaction to give the final products 24aee. The stereo-
chemical outcome of the synthesis could be explained by a high
sensitivity of the cyclization step to multiple factors. The possibility
of the formation of intermediates 28aee from 25aed in two steps
can not also be excluded.
The structures of 29aec were established by IR, 1H and 13C NMR
spectroscopy, mass spectrometry. The values of vicinal coupling
constants between N(4)H, H-5, HA-6, and HB-6 have proved that
triazepinones 29aec exist predominantly in a puckered confor-
mation with a pseudo axial orientation of the aryl-group at the C-5
position (in DMSO-d6).
Scheme 8. A plausible pathway for the transformation of 20aee into macrocycles 24aee.

A.A. Fesenko, A.D. Shutalev / Tetrahedron 71 (2015) 9528e9543
9533
Table 6
TsOH-catalyzed transformation of hydrazones of 4-(3-oxo-3-phenylprop-1-yl)semicarbazides 20feh into 7-phenyl-2,4,5,6-tetrahydro-3H-1,2,4-triazepin-3-ones 29aec
Entry
20
R
Conc. of 20 (mol/L)
Equiv of TsOH
Solvent
Reaction conditions
Product
Purity of crude 29 (%)b
Yield (%)c
1
2
3
4
5
6
7
8
9
20f
20f
20f
20f
20f
20f
20f
20f
20g
20h
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
0.102
0.102
0.102
0.146
0.112
0.019
0.030
0.093
0.030
0.023
0.10
0.51
1.04
1.21
0.98
1.01
1.04
1.10
1.05
1.02
NfPO
NfPO
NfPO
MeCN
EtOH
EtOH
EtOH
EtOH
EtOH
Reflux, 2.5 h
Reflux, 50 min
Reflux, 1 h
NRa
NRa
29a
29a
29a
29a
29a
29a
29b
29c
d
d
19
23
28
49
39
3
d
d
d
d
d
d
39
d
45
41
Reflux, 5 h
Reflux, 1 h 50 min
Reflux, 1 h 50 min
Reflux, 1 h 50 min
rt, 2 h
Reflux, 1 h 50 min
Reflux, 1 h 50 min
4-MeC6H4
4-ClC6H4
d
10
EtOH
d
a
NR¼no reaction occurred (TLC analysis).
b
Purity was estimated as ratio of the expected integral intensity of the aromatic protons region (10H for 29a) to the observed integral intensity in this region in the 1H NMR
spectrum of the crude product multiplied by 100. The starting material was consumed (entries 3e8).
c
For analytically pure samples after column chromatography.
Thus, in contrast to 20aee, semicarbazides 20feh under acidic
conditions gave the corresponding 7-membered cyclic semi-
carbazones. The reason for this difference is apparently due to
opposite configurations of the major isomers of compounds 20aee
and 20feh. The major isomers of 20feh (75e84%, Table 4) have the
E-configuration, which is favorable for intramolecular nucleophilic
attack of the NH2 group of hydrazone moiety in 20feh on the
carbonyl carbon to give 29aec.
purchased from commercial sources and used without additional
purification. FTIR spectra were recorded using a Bruker Vector 22
spectrophotometer in Nujol. Band characteristics in the IR spectra
are defined as very strong (vs), strong (s), medium (m), weak (w),
shoulder (sh), and broad (br). NMR spectra were acquired using
a Bruker DPX-300 spectrometer at 300.13 (1H) and 75.48 (13C) MHz
and a Bruker Avance 600 spectrometer at 600.13 MHz (1H and
1H,1H-NOESY for 20h) as solutions in DMSO-d6. 1H NMR chemical
shifts are referenced to the residual proton signal in DMSO-d6
(2.50 ppm). In 13C NMR spectra, central signals of DMSO-d6
(39.50 ppm) were used as references. Multiplicities are reported as
singlet (s), doublet (d), triplet (t), quartet (q), and some combina-
tions of these, multiplet (m). Selective 1He1H decoupling and
DEPT-135 experiments were used to aid in the assignment of 1H
and 13C NMR signals. Mass spectra were obtained on a Finnigan
MAT INCOS 50 instrument (electron impact, 70 eV). Elemental
analyses (CHN) were performed using a Thermo Finnigan Flash
EA1112 apparatus. Thin-layer chromatography was carried out on
Aldrich silica gel 60 F254 aluminum backed plates in chloroform/
methanol (9:1, v/v) and chloroform/methanol (5:1, v/v) as solvent
systems. Spots were visualized with UV light. Column chromatog-
raphy was performed with MachereyeNagel silica gel 60
(0.063e0.200 mm). All yields refer to isolated, spectroscopically
and TLC pure compounds. The color of substances was white, if not
otherwise mentioned. Evaporation of solvent from all the reaction
mixtures formed after the preparation of carbamates 17 was carried
out, at the beginning, upon cooling (temperature of water bath
about 5e10 ꢀC), and low vacuum (about 100 mmHg), otherwise the
vigorous foaming complicated evaporation. In some complex cases
the reaction mixture was transferred into a larger flask prior the
evaporation of solvent.
3. Conclusion
We have demonstrated that the acid-catalyzed cyclization of the
hydrazones of 4-(3-oxobutyl)semicarbazides involves two mole-
cules of the starting material to give a general access to novel 14-
membered cyclic bis-semicarbazones. In contrast, the hydrazones
of 4-(3-oxo-3-phenylpropyl)semicarbazides under similar condi-
tions transform into 7-membered cyclic semicarbazones. Such
a difference was explained by the opposite stereochemistry of the
major isomers of the starting semicarbazides. These compounds
were prepared by the treatment of N-(
g-oxoalkyl)carbamates with
refluxing hydrazine. For the preparation of N-(
g-oxoalkyl)carba-
mates18 a simple multi-gram three-step approach has been de-
veloped. The method is based on the amidoalkylation of 1,3-
diketone enolates with N-(a-tosylbenzyl)carbamates followed by
base-promoted retro-Claisen reaction. We believe that the obtained
classes of heterocycles, which are representatives of rare hetero-
cyclic scaffolds, may find broad applications in synthetic organic
and medicinal chemistry, e.g., as new polyazamacrocyclic ligands
for metal complexes, as a basis for the development of new ther-
apeutics, etc.
4. Experimental section
4.1. General
4.2. Synthesis of ethyl N-[(b-acyl-g-oxo)alkyl]carbamates
4.2.1. Ethyl N-[(phenyl)(tosyl)methyl]carbamate (15a). To a stirred
emulsion of benzaldehyde (5.660 g, 53.34 mmol) in H2O (25 mL)
were added p-toluenesulfinic acid (13) (8.342 g, 53.40 mmol) and
H2O (25 mL) and the resulting mixture was stirred for 20 min at
room temperature. To the formed suspension were added ethyl
carbamate (12) (4.767 g, 53.51 mmol) and H2O (16 mL) and the
suspension was heated under stirring in a water bath (70 ꢀC). 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 total. After completion of the reaction, the obtained
suspension was cooled to 0 ꢀC. The precipitate was filtered, washed
with ice-cold H2O and petroleum ether, and dried to give carba-
mate 15a (15.622 g, 88%) which was used without additional pu-
All solvents were distilled before use. Petroleum ether had
a distillation range of 40e60 ꢀC. Dry solvents (MeCN, THF) were
obtained according to standard procedures. p-Toluenesulfinic acid
(13) was synthesized by treatment of a saturated aqueous solution
of sodium p-toluenesulfinate25 with hydrochloric acid at 0 ꢀC, dried
over P2O5, and stored at ꢁ18 ꢀC. Sodium hydride (60% suspension in
mineral oil) was thoroughly washed with dry pentane and dried
under vacuum prior to use. Anhydrous hydrazine was obtained by
refluxing with an equal weight of KOH pellets for 3 h under argon
followed by distillation, and this operation was repeated twice. 3-
Methylpentane-2,4-dione (14b) was prepared as described in the
literature26 with 86.7 wt % purity (a 3:1 mixture of ketone and enol
form in CDCl3) (3,3-dimethylpentane-2,4-dione was the admixture,
12 mol % according to 1H NMR data). All other reagents were
rification. 1H NMR (300.13 MHz, DMSO-d6)
d: 8.93 (1H, d,
3J¼10.8 Hz, NH), 7.56e7.72 (4H, m, ArH), 7.35e7.45 (5H, m, ArH),

9534
A.A. Fesenko, A.D. Shutalev / Tetrahedron 71 (2015) 9528e9543
5.99 (1H, d, 3J¼10.8 Hz, CHN), 3.76e3.92 (2H, m, OCH2), 2.40 (3H, s,
CH3 in Ts), 1.01 (3H, t, 3J¼7.1 Hz, CH3 in OEt); 13C NMR (75.48 MHz,
precipitate was filtered, washed with ice-cold H2O and petroleum
ether, and dried to give carbamate 15e (12.726 g, 93%) which was
used without additional purification. 1H NMR (300.13 MHz, DMSO-
DMSO-d6) d: 155.26 (C]O),144.57 (C), 133.75 (C), 130.39 (C), 129.59
(2CH), 129.46 (2CH), 129.26 (CH), 129.16 (2CH), 128.07 (2CH), 74.88
(CHN), 60.62 (OCH2), 21.08 (CH3 in Ts), 14.35 (CH3 in OEt).
d6)
d
: 8.96 (1H, d, 3J¼10.8 Hz, NH), 7.62e7.73 (4H, m, ArH),
7.40e7.51 (4H, m, ArH), 6.07 (1H, d, 3J¼10.8 Hz, CHN), 3.75e3.91
(2H, m, OCH2), 2.40 (3H, s, CH3 in Ts), 1.00 (3H, t, 3J¼7.1 Hz, CH3 in
4.2.2. Ethyl
N-[(4-methylphenyl)(tosyl)methyl]carbamate
OEt); 13C NMR (75.48 MHz, DMSO-d6)
d: 155.20 (C]O), 144.78 (C),
(15b). Compound 15b (37.72 g, 86%) was prepared from 4-
methylbenzaldehyde (15.14 g, 126 mmol), p-toluenesulfinic acid
(13) (19.71 g, 126 mmol) and ethyl carbamate (12) (12.97 g,
146 mmol) in H2O (126 mL) (70 ꢀC, 1 h 30 min) as described for 15a.
134.29 (C), 133.52 (C), 131.48 (2CH), 129.56 (2CH), 129.45 (C), 129.25
(2CH), 128.19 (2CH), 74.05 (CHN), 60.72 (OCH2), 21.14 (CH3 in Ts),
14.38 (CH3 in OEt).
1H NMR (300.13 MHz, DMSO-d6)
d
: 8.87 (1H, d, 3J¼10.8 Hz, NH),
4.2.6. Ethyl N-(1-tosylbut-1-yl)carbamate (15f). Compound 15f
(33.76 g, 94%) was prepared from butanal (8.65 g, 120 mmol), p-
toluenesulfinic acid (13) (18.75 g, 120 mmol) and ethyl carbamate
(12) (12.83 g, 144 mmol) in H2O (120 mL) (70 ꢀC, 1 h 30 min) as
7.65e7.72 (2H, m, ArH), 7.38e7.51 (4H, m, ArH), 7.16e7.22 (2H, m,
ArH), 5.93 (1H, d, 3J¼10.8 Hz, CHN), 3.75e3.91 (2H, m, OCH2), 2.40
(3H, s, CH3 in Ts), 2.32 (3H, s, CH3 in 4-MeC6H4), 1.00 (3H, t,
3J¼7.1 Hz, CH3 in OEt); 13C NMR (75.48 MHz, DMSO-d6)
d
: 155.22
described for 15a. 1H NMR (300.13 MHz, DMSO-d6)
d: 8.12 (1H, d,
(C]O), 144.48 (C), 138.79 (C), 133.87 (C), 129.49 (2CH), 129.44
(2CH), 129.14 (2CH), 128.63 (2CH), 127.33 (C), 74.72 (CHN), 60.58
(OCH2), 21.07 (CH3 in Ts), 20.78 (CH3 in 4-MeC6H4), 14.35 (CH3 in
OEt).
3J¼9.8 Hz, NH), 7.64e7.70 (2H, m, ArH), 7.39e7.45 (2H, m, ArH), 4.70
(1H, ddd, 3J¼11.4, 3J¼9.8, 3J¼3.3 Hz, CHN), 3.72e3.88 (2H, m, OCH2),
2.39 (3H, s, CH3 in Ts), 1.82e1.93 (1H, m, CHA in CH2CH2CH3),
1.57e1.70 (1H, m, CHB in CH2CH2CH3), 1.17e1.48 (2H, m,
CH2CH2CH3), 0.99 (3H, t, 3J¼7.1 Hz, CH3 in OEt), 0.84 (3H, t,
3J¼7.4 Hz, CH3 in Pr).
4.2.3. Ethyl
N-[(4-methoxylphenyl)(tosyl)methyl]carbamate
(15c). To 4-methoxylbenzaldehyde (0.451 g, 3.31 mmol) were
added p-toluenesulfinic acid (13) (0.519 g, 3.33 mmol), ethyl car-
bamate (12) (0.351 g, 3.94 mmol) and H2O (3 mL) and the resulting
mixture was stirred at room temperature. At the beginning of the
reaction the oily material formed and after 1 h it completely so-
lidified. The obtained solid was triturated and the resulting sus-
pension was stirred at room temperature for 24 h in total. After
completion of the reaction, the suspension was cooled to 0 ꢀC, the
precipitate was filtered, washed with ice-cold H2O and petroleum
ether, and dried to give carbamate 15c (1.112 g, 92%) which was
used without additional purification. 1H NMR (300.13 MHz, DMSO-
4.3. Synthesis of ethyl N-[(
b-acyl-g-oxo)alkyl]carbamates
4.3.1. Ethyl N-[(2-acetyl-3-oxo-1-phenyl)but-1-yl]carbamate
(17a). To an ice-cooled stirred suspension of NaH (0.316 g,
13.18 mmol) in dry MeCN (10 mL) was added a solution of acety-
lacetone (16a) (1.341 g, 13.39 mmol) in MeCN (12 mL), and the
resulting mixture was stirred for 30 min. The ice-bath was re-
moved, and to the obtained suspension were added sulfone 15a
(4.007 g, 12.02 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 NaHCO3
(10 mL) and petroleum ether (10 mL), the obtained suspension was
left overnight at room temperature and cooled to 0 ꢀC. The pre-
cipitate was filtered, washed with ice-cold H2O and petroleum
ether, and dried to give compound 17a (3.099 g, 93%). Mp
100.5e101.5 ꢀC (EtOHeH2O, 1:1) (lit.17a mp 87e88 ꢀC). 1H NMR
d6)
d
: 8.86 (1H, d, 3J¼10.8 Hz, NH), 7.64e7.71 (2H, m, ArH),
7.49e7.56 (2H, m, ArH), 7.38e7.45 (2H, m, ArH), 7.91e7.97 (2H, m,
ArH), 5.92 (1H, d, 3J¼10.8 Hz, CHN), 3.75e3.91 (2H, m, OCH2), 3.77
(3H, s, OCH3), 2.40 (3H, s, CH3 in Ts), 1.00 (3H, t, 3J¼7.1 Hz, CH3 in
OEt); 13C NMR (75.48 MHz, DMSO-d6)
d: 160.02 (C), 155.23 (C]O),
144.46 (C), 133.91 (C), 131.01 (2CH), 129.46 (2CH), 129.16 (2CH),
122.14 (C), 113.53 (2CH), 74.45 (CHN), 60.59 (OCH2), 55.20 (OCH3),
21.12 (CH3 in Ts), 14.40 (CH3 in OEt).
(300.13 MHz, DMSO-d6)
d
: 7.78 (1H, d, 3J¼9.2 Hz, NH), 7.19e7.35
(5H, m, ArH), 5.15 (1H, dd, 3J¼11.3, 3J¼9.2 Hz, CHN), 4.48 (1H, d,
3J¼11.3 Hz, CHAc2), 3.83e3.98 (2H, m, OCH2), 2.23 (3H, s, CH3 in Ac),
1.88 (3H, s, CH3 in Ac), 1.09 (3H, t, 3J¼7.1 Hz, CH3 in OEt); 13C NMR
4.2.4. Ethyl
N-[(4-tert-butylphenyl)(tosyl)methyl]carbamate
(15d). Compound 15d (11.833 g, 81%) was prepared from 4-tert-
butylbenzaldehyde (6.090 g, 37.54 mmol), p-toluenesulfinic acid
(13) (5.879 g, 37.63 mmol) and ethyl carbamate (12) (4.040 g,
45.34 mmol) in H2O (74 mL) (rt, 24 h) as described for 15c. Solid-
ification of initially formed oily material completed in 4 h. 1H NMR
(75.48 MHz, DMSO-d6) d: 201.48 (C]O in Ac), 201.32 (C]O in Ac),
155.32 (C]O in COOEt), 140.64 (C), 128.38 (2CH), 127.51 (CH),
127.28 (2CH), 71.73 (CHAc2), 59.95 (OCH2), 54.13 (CHN), 30.78 (CH3
in Ac), 30.14 (CH3 in Ac),14.45 (CH3 in OEt); IR (Nujol)
(s) ( NH), 3086 (w), 3064 (w), 3035 (w) ( CHarom), 1735 (s) (
in Ac), 1693 (vs) (amide-I), 1603 (w), 1584 (w) ( CCarom), 1529 (s)
(amide-II), 1255 (s), 1146 (s) ( CeO), 758 (m), 704 (s) ( CHarom).
n
, cmꢁ1: 3372
C]O
n
n
n
(300.13 MHz, DMSO-d6)
d
: 8.91 (1H, d, 3J¼10.7 Hz, NH), 7.68e7.75
n
(2H, m, ArH), 7.51e7.58 (2H, m, ArH), 7.37e7.45 (4H, m, ArH), 5.94
(1H, d, 3J¼10.7 Hz, CHN), 3.73e3.88 (2H, m, OCH2), 2.40 (3H, s, CH3
n
d
Anal. Calcd for C15H19NO4: C, 64.97; H, 6.91; N, 5.05. Found: C,
64.98; H, 6.97; N, 5.26.
in Ts), 1.29 (9H, s, CH3 in t-Bu), 0.98 (3H, t, 3J¼7.1 Hz, CH3 in OEt); 13
C
NMR (75.48 MHz, DMSO-d6) d: 155.19 (C]O), 151.84 (C), 144.52 (C),
133.93 (C), 129.45 (2CH), 129.39 (2CH), 129.17 (2CH), 127.28 (C),
124.94 (2CH), 74.56 (CHN), 60.57 (OCH2), 34.42 (CMe3), 31.02
(3ꢂCH3 in t-Bu), 21.11 (CH3 in Ts), 14.39 (CH3 in OEt).
4.3.2. Ethyl N-{[2-acetyl-1-(4-methylphenyl)-3-oxo]but-1-yl}carba-
mate (17b). Compound 17b (3.270 g, 91%) was prepared from
acetylacetone (16a) (1.270 g, 12.67 mmol), NaH (0.299 g,
12.46 mmol) and sulfone 15b (4.230 g, 12.38 mmol) in dry MeCN
(26 mL) (rt, 9 h 30 min) as described for 17a. (Note: the reaction was
carried out in a 50 mL round-bottomed flask, the reaction mixture
was transferred into a 250 mL round-bottomed flask prior to
evaporation since the vigorous foam formation during the evapo-
ration complicated removal of the solvent when the flask of lower
volume was used). Mp 94e95 ꢀC (EtOHeH2O, 1:1). 1H NMR
4.2.5. Ethyl N-[(4-chlorophenyl)(tosyl)methyl]carbamate (15e). To
a finely powdered 4-chlorobenzaldehyde (5.251 g, 37.36 mmol)
were added p-toluenesulfinic acid (13) (5.856 g, 37.49 mmol), ethyl
carbamate (12) (3.969 g, 37.49 mmol) and H2O (42 mL) and the
reaction mixture was heated under stirring in a water bath (70 ꢀC).
After 15 min, an oily material formed and after 30 min it completely
solidified. The obtained solid was triturated and the resulting sus-
pension was heated (70 ꢀC, water bath) under stirring for 1 h
30 min in total. The obtained suspension was cooled to 0 ꢀC. The
(300.13 MHz, DMSO-d6)
d
: 7.70 (1H, d, 3J¼9.3 Hz, NH), 7.16e7.21
(2H, m, ArH), 7.08e7.13 (2H, m, ArH), 5.12 (1H, dd, 3J¼11.2,
3J¼9.3 Hz, CHN), 4.45 (1H, d, 3J¼11.2 Hz, CHAc2), 3.82e3.98 (2H, m,

A.A. Fesenko, A.D. Shutalev / Tetrahedron 71 (2015) 9528e9543
9535
OCH2), 2.25 (3H, s, CH3 in 4-MeC6H4), 2.22 (3H, s, CH3 in Ac), 1.88
(s) (amide-I), 1544 (s) (amide-II), 1300 (s) (
C12H21NO4: C, 59.24; H, 8.70; N, 5.76. Found: C, 59.18; H, 8.80; N,
5.90.
n
CeO). Anal. Calcd for
(3H, s, CH3 in Ac), 1.09 (3H, t, 3J¼7.1 Hz, CH3 in OEt); 13C NMR
(75.48 MHz, DMSO-d6)
d
: 201.53 (C]O in Ac), 201.28 (C]O in Ac),
155.25 (C]O in COOEt), 137.64 (C), 136.61 (C), 128.87 (2CH), 127.14
(2CH), 71.79 (CHAc2), 59.85 (OCH2), 53.84 (CHN), 30.67 (CH3 in Ac),
30.04 (CH3 in Ac), 20.60 (CH3 in 4-MeC6H4), 14.42 (CH3 in OEt); IR
4.3.6. Ethyl N-[(2-acetyl-2-methyl-3-oxo-1-phenyl)but-1-yl]carba-
mate (17f). Compound 17f (3.053 g, 81%) was prepared from 3-
methylpentane-2,4-dione (16b) (86.7% wt, 1.716 g, 13.04 mmol),
NaH (0.312 g, 13.00 mmol) and sulfone 15a (4.333 g, 12.99 mmol) in
dry THF (26 mL) (rt, 8 h 5 min) as described for 17a. Mp 84e85 ꢀC
(Nujol)
O in Ac), 1683 (s) (amide-I), 1618 (w) (
1256 (s), 1157 (s) ( CeO), 823 (m) (
16H21NO4: C, 65.96; H, 7.27; N, 4.81. Found: C, 65.69; H, 7.15; N,
n
, cmꢁ1: 3327 (s) (
n
NH), 3037 (m) (
CCarom), 1532 (s) (amide-II),
CHarom). Anal. Calcd for
n CHarom), 1701 (s) (n C]
n
n
d
C
4.82.
(EtOHeH2O, 1:1). 1H NMR (300.13 MHz, DMSO-d6)
d: 7.80 (1H, d,
3J¼10.6 Hz, NH), 7.19e7.33 (5H, m, ArH), 5.77 (1H, d, 3J¼10.6 Hz,
CHN), 3.86e4.03 (2H, m, OCH2), 2.11 (3H, s, CH3 in Ac), 1.92 (3H, s,
CH3 in Ac), 1.29 (3H, s, CH3CAc2), 1.12 (3H, t, 3J¼7.1 Hz, CH3 in OEt);
4.3.3. Ethyl N-{[2-acetyl-1-(4-methoxyphenyl)-3-oxo]but-1-yl}car-
bamate (17c). Compound 17c (2.344 g, 90%) was prepared from
acetylacetone (16a) (0.885 g, 8.84 mmol), NaH (0.204 g, 8.51 mmol)
and sulfone 15c (3.089 g, 8.50 mmol) in dry MeCN (26 mL) (rt, 8 h
40 min) as described for 17a. Mp 99e101 ꢀC (EtOHeH2O, 1:2). 1H
13C NMR (75.48 MHz, DMSO-d6)
d: 206.18 (C]O in Ac), 204.19 (C]
O in Ac), 155.82 (C]O in COOEt), 139.31 (C), 128.31 (2CH), 127.85
(2CH), 127.27 (CH), 70.65 (CAc2), 60.17 (OCH2), 56.40 (CHN), 27.39
(CH3 in Ac), 26.46 (CH3 in Ac), 14.50 (CH3 in OEt), 14.19 (CH3CAc2);
NMR (300.13 MHz, DMSO-d6)
d
: 7.71 (1H, d, 3J¼9.3 Hz, NH),
IR (Nujol)
1722 (s) (
CCarom), 1525 (s) (amide-II), 1499 (w) (
CeO), 768 (m), 713 (s) (
n
n
, cmꢁ1: 3352 (s) (
n
NH), 3057 (w), 3029 (w) (
C]O in Ac), 1699 (vs) (amide-I), 1600 (w), 1580 (w) (
CCarom), 1239 (s), 1043 (s) (
n CHarom),
7.19e7.25 (2H, m, ArH), 6.83e6.89 (2H, m, ArH), 5.10 (1H, dd,
3J¼11.4, 3J¼9.3 Hz, CHN), 4.43 (1H, d, 3J¼11.4 Hz, CHAc2), 3.83e3.98
(2H, m, OCH2), 3.71 (3H, s, OCH3), 2.22 (3H, s, CH3 in Ac), 1.88 (3H, s,
CH3 in Ac), 1.09 (3H, t, 3J¼7.1 Hz, CH3 in OEt); 13C NMR (75.48 MHz,
n
n
n
d
CHarom). Anal. Calcd for C16H21NO4: C,
65.96; H, 7.27; N, 4.81. Found: C, 66.01; H, 7.27; N, 4.81.
DMSO-d6) d: 201.58 (C]O in Ac), 201.36 (C]O in Ac), 158.47 (C),
155.26 (C]O in COOEt), 132.63 (C), 128.45 (2CH), 113.68 (2CH),
72.01 (CHAc2), 59.88 (OCH2), 55.00 (OCH3), 53.60 (CHN), 30.74 (CH3
4.3.7. Ethyl N-{[2-acetyl-1-(4-methylphenyl)-2-methyl-3-oxo]but-1-
yl}carbamate (17g). Compound 17g (2.508 g, 87%) was prepared
from 3-methylpentane-2,4-dione (16b) (86.7% wt, 1.246 g,
9.47 mmol), NaH (0.227 g, 9.44 mmol) and sulfone 15b (3.275 g,
9.42 mmol) in dry THF (24 mL) (rt, 8 h 10 min) as described for 17a.
in Ac), 30.04 (CH3 in Ac),14.46 (CH3 in OEt); IR (Nujol)
(s) ( NH), 3061 (w), 3039 (w) ( CHarom), 1727 (s) (
1690 (s) (amide-I), 1612 (m), 1586 (w) (
(amide-II),1257 (s),1029 (s) ( CeO), 827 (m) (
n
n
, cmꢁ1: 3362
n
n
C]O in Ac),
n
CCarom), 1531 (s), 1520 (s)
CHarom). Anal. Calcd
n
d
Mp 93e94 ꢀC (EtOHeH2O, 1:1). 1H NMR (300.13 MHz, DMSO-d6)
d:
for C16H21NO5: C, 62.53; H, 6.89; N, 4.56. Found: C, 62.66; H, 6.90; N,
4.70.
7.73 (1H, d, 3J¼10.6 Hz, NH), 7.15e7.21 (2H, m, ArH), 7.05e7.11 (2H,
m, ArH), 5.72 (1H, d, 3J¼10.6 Hz, CHN), 3.85e4.02 (2H, m, OCH2),
2.24 (3H, s, CH3 in 4-MeC6H4), 2.10 (3H, s, CH3 in Ac),1.92 (3H, s, CH3
4.3.4. Ethyl N-{[2-acetyl-1-(4-tert-butylphenyl)-3-oxo]but-1-yl}car-
bamate (17d). Compound 17d (2.519 g, 93%) was prepared from
acetylacetone (16a) (0.848 g, 8.47 mmol), NaH (0.195 g, 8.14 mmol)
and sulfone 15d (3.170 g, 8.14 mmol) in dry MeCN (22 mL) (rt, 8 h
10 min) as described for 17a. Mp 100.5e101.5 ꢀC (EtOHeH2O, 1:1).
in Ac), 1.28 (3H, s, CH3CAc2), 1.12 (3H, t, 3J¼7.1 Hz, CH3 in OEt); 13
C
NMR (75.48 MHz, DMSO-d6) d: 206.20 (C]O in Ac), 204.31 (C]O in
Ac), 155.79 (C]O in COOEt), 136.38 (C), 136.32 (C), 128.41 (2CH),
128.23 (2CH), 70.68 (CAc2), 60.12 (OCH2), 56.25 (CHN), 27.39 (CH3
in Ac), 26.46 (CH3 in Ac), 20.58 (CH3 in 4-MeC6H4), 14.51 (CH3 in
1H NMR (300.13 MHz, DMSO-d6)
d
: 7.72 (1H, d, 3J¼9.3 Hz, NH),
OEt), 14.20 (CH3CAc2); IR (Nujol)
CHarom), 1720 (s) ( C]O in Ac), 1693 (s) (amide-I), 1615 (w) (
CCarom), 1525 (s) (amide-II), 1233 (s), 1039 (s) ( CeO), 820 (m) (
n n NH), 3091 (w)
, cmꢁ1: 3387 (s) (
7.30e7.35 (2H, m, ArH), 7.20e7.25 (2H, m, ArH), 5.14 (1H, dd,
3J¼11.3, 3J¼9.3 Hz, CHN), 4.47 (1H, d, 3J¼11.3 Hz, CHC]O),
3.82e3.98 (2H, m, OCH2), 2.22 (3H, s, CH3 in Ac), 1.89 (3H, s, CH3 in
(n
n
n
n
d
CHarom). Anal. Calcd for C17H23NO4: C, 66.87; H, 7.59; N, 4.59.
Found: C, 66.99; H, 7.67; N, 4.77.
Ac), 1.24 (9H, s, CH3 in t-Bu), 1.10 (3H, t, 3J¼7.1 Hz, CH3 in OEt); 13
C
NMR (75.48 MHz, DMSO-d6) d: 201.63 (C]O in Ac), 201.34 (C]O in
Ac), 155.29 (C]O in COOEt), 149.76 (C), 137.66 (C), 126.92 (2CH),
125.12 (2CH), 71.70 (CHAc2), 59.91 (OCH2), 53.66 (CHN), 34.20
(CMe3), 31.09 (3ꢂCH3 in t-Bu), 30.64 (CH3 in Ac), 30.07 (CH3 in Ac),
4.3.8. Ethyl N-{[2-acetyl-1-(4-methoxylphenyl)-2-methyl-3-oxo]but-
1-yl}carbamate (17h). Compound 17h (2.731 g, 83%) was prepared
from 3-methylpentane-2,4-dione (16b) (86.7% wt, 1.354 g,
10.29 mmol), NaH (0.246 g, 10.26 mmol) and sulfone 15c (3.726 g,
10.25 mmol) in dry THF (25 mL) (rt, 8 h 5 min) as described for 17a.
14.45 (CH3 in OEt); IR (Nujol)
3348 (br m) ( NH), 3060 (w) (
1701 (s) (amide-I), 1520 (s) (amide-II), 1270 (s), 1051 (m) (
832 (w) ( CHarom). Anal. Calcd for C19H27NO4: C, 68.44; H, 8.16; N,
4.20. Found: C, 68.10; H, 8.36; N, 4.19.
n
, cmꢁ1: 3530 (br w), 3396 (br m),
n
n
CHarom), 1734 (s) (
n
C]O in Ac),
CeO),
n
Mp 91e92 ꢀC (EtOHeH2O, 1:1). 1H NMR (300.13 MHz, DMSO-d6)
d:
d
7.72 (1H, d, 3J¼10.6 Hz, NH), 7.19e7.25 (2H, m, ArH), 6.81e6.87 (2H,
m, ArH), 5.71 (1H, d, 3J¼10.6 Hz, CHN), 3.85e4.02 (2H, m, OCH2),
3.71 (3H, s, OCH3), 2.10 (3H, s, CH3 in Ac),1.91 (3H, s, CH3 in Ac),1.28
(3H, s, CH3CAc2), 1.12 (3H, t, 3J¼7.1 Hz, CH3 in OEt); 13C NMR
4.3.5. Ethyl
N-[(3-acetyl-2-oxo)hept-4-yl]carbamate
(17e). Compound 17e (2.401 g, 89%) was prepared from acetyla-
cetone (16a) (1.128 g, 11.26 mmol), NaH (0.265 g, 11.04 mmol) and
sulfone 15f (3.305 g, 11.04 mmol) in dry MeCN (25 mL) (rt, 8 h
10 min) as described for 17a. Mp 89.5e90.5 ꢀC (EtOHeH2O, 1:2). 1H
(75.48 MHz, DMSO-d6) d: 206.27 (C]O in Ac), 204.37 (C]O in Ac),
158.30 (C), 155.78 (C]O in COOEt), 131.23 (C), 129.49 (2CH), 113.17
(2CH), 70.78 (CAc2), 60.12 (OCH2), 55.93 (CHN), 54.97 (OCH3), 27.38
(CH3 in Ac), 26.46 (CH3 in Ac),14.51 (CH3 in OEt),14.19 (CH3CAc2); IR
NMR (300.13 MHz, DMSO-d6)
d
: 7.02 (1H, d, 3J¼9.4 Hz, NH),
(Nujol)
(vs), 1706 (sh) (
CCarom), 1528 (vs) (amide-II), 1234 (s), 1032 (s) (
n
, cmꢁ1: 3385 (s) (
n
NH), 3071 (w), 3037 (w) (
C]O in Ac and amide-I), 1608 (m), 1581 (w) (
CeO), 841 (m) (
n CHarom),1714
4.07e4.17 (1H, m, CHN), 3.87e4.02 (3H, m, OCH2 and CHC]O), 2.17
(3H, s, CH3 in Ac), 2.10 (3H, s, CH3 in Ac), 1.15e1.34 (4H, m,
CH2CH2CH3),1.12 (3H, t, 3J¼7.1 Hz, CH3 in OEt), 0.82 (3H, t, 3J¼7.0 Hz,
n
n
d
n
CHarom). Anal. Calcd for C17H23NO5: C, 63.54; H, 7.21; N, 4.36. Found:
C, 63.58; H, 7.18; N, 4.39.
CH3 in Pr); 13C NMR (75.48 MHz, DMSO-d6)
d: 203.05 (C]O in Ac),
202.98 (C]O in Ac), 155.93 (C]O in COOEt), 71.74 (CHAc2), 59.72
(OCH2), 49.83 (CHN), 35.06 (CH2CH2CH3), 30.80 (CH3 in Ac), 29.53
(CH3 in Ac), 18.57 (CH2CH2CH3), 14.55 (CH3 in OEt), 13.57 (CH3 in
4.3.9. Ethyl
N-{[2-acetyl-1-(4-tert-butylphenyl)-2-methyl-3-oxo]
but-1-yl}carbamate (17i). Compound 17i (2.002 g, 84%) was pre-
pared from 3-methylpentane-2,4-dione (16b) (86.7% wt, 0.902 g,
Pr); IR (Nujol) n n NH), 1723 (s) (n C]O in Ac), 1691
, cmꢁ1: 3322 (s) (

9536
A.A. Fesenko, A.D. Shutalev / Tetrahedron 71 (2015) 9528e9543
6.85 mmol), NaH (0.164 g, 6.84 mmol) and sulfone 15d (2.664 g,
6.84 mmol) in dry THF (22 mL) (rt, 8 h 20 min) as described for 17a.
Mp 100.5e101.5 ꢀC (EtOHeH2O, 1:1). 1H NMR (300.13 MHz, DMSO-
808 (m), 764 (m), 690 (m)
26H25NO4$0.05H2O: C, 75.00; H, 6.08; N, 3.36. Found: C, 74.61; H,
6.03; N, 3.47.
(d CHarom). Anal. Calcd for
C
d6)
d
: 7.75 (1H, d, 3J¼10.6 Hz, NH), 7.27e7.32 (2H, m, ArH),
7.20e7.25 (2H, m, ArH), 5.74 (1H, d, 3J¼10.6 Hz, CHN), 3.85e4.02
(2H, m, OCH2), 2.10 (3H, s, CH3 in Ac), 1.93 (3H, s, CH3 in Ac), 1.29
(3H, s, CH3CAc2), 1.24 (9H, s, CH3 in t-Bu), 1.12 (3H, t, 3J¼7.1 Hz, CH3
4.3.12. Ethyl N-{[2-benzoyl-1-(4-methoxyphenyl)-3-oxo-3-phenyl]
prop-1-yl}carbamate (17l). Compound 17l (3.598 g, 93%) was pre-
pared from dibenzoylmethane (16c) (2.112 g, 9.42 mmol), NaH
(0.215 g, 8.98 mmol) and sulfone 15c (3.263 g, 8.98 mmol) in dry
THF (24 mL) (rt, 8 h) as described for 17j. Mp 156e157.5 ꢀC (EtOH).
in OEt); 13C NMR (75.48 MHz, DMSO-d6)
d: 206.14 (C]O in Ac),
204.29 (C]O in Ac), 155.81 (C]O in COOEt), 149.44 (C), 136.36 (C),
128.05 (2CH), 124.58 (2CH), 70.71 (CAc2), 60.13 (OCH2), 56.02
(CHN), 34.14 (CMe3), 31.08 (3ꢂCH3 in t-Bu), 27.33 (CH3 in Ac), 26.45
1H NMR (300.13 MHz, DMSO-d6)
d: 8.00e8.05 (2H, m, ArH),
7.75e7.80 (2H, m, ArH), 7.67 (1H, d, 3J¼9.2 Hz, NH), 7.47e7.66 (4H,
m, ArH), 7.37e7.45 (2H, m, ArH), 7.28e7.34 (2H, m, ArH), 6.71e6.77
(2H, m, ArH), 6.35 (1H, d, 3J¼10.2 Hz, CHC]O), 5.49 (1H, dd,
3J¼10.2, 3J¼9.2 Hz, CHN), 3.77e3.91 (2H, m, OCH2), 3.62 (3H, s,
OCH3), 1.03 (3H, t, 3J¼7.1 Hz, CH3); 13C NMR (75.48 MHz, DMSO-d6)
(CH3 in Ac), 14.51 (CH3 in OEt), 14.24 (CH3CAc2); IR (Nujol) n :
, cmꢁ1
3356 (s) (
(amide-II),1236 (s),1041 (s) (
n
NH), 1721 (s) (
n
C]O in Ac), 1700 (s) (amide-I), 1533 (s)
CeO), 846 (m) ( CHarom). Anal. Calcd
n
d
for C20H29NO4: C, 69.14; H, 8.41; N, 4.03. Found: C, 69.09; H, 8.58; N,
4.03.
d: 193.25 (C]O in Bz), 193.17 (C]O in Bz), 158.26 (C), 155.11 (C]O
in COOEt), 136.35 (C), 135.70 (C), 133.82 (CH), 133.77 (CH), 132.64
(C), 128.93 (2CH), 128.86 (2CH), 128.72 (2CH), 128.62 (2CH), 128.35
(2CH), 113.43 (2CH), 60.01 (CHBz2), 59.78 (OCH2), 54.94 (OCH3),
4.3.10. Ethyl N-[(2-benzoyl-3-oxo-1,3-diphenyl)prop-1-yl]carbamate
(17j). To a mixture of dibenzoylmethane (16c) (2.138 g, 9.53 mmol)
and NaH (0.218 g, 9.07 mmol) was added dry THF (17 mL), the
mixture was stirred in an ice-cold bath for 15 min, and to the
resulting solution were added sulfone 15a (3.024 g, 9.07 mmol) and
THF (7 mL). The suspension was stirred at room temperature for
8 h, and solvent was removed in a vacuum. To a solid residue was
added saturated aqueous NaHCO3 (10 mL), the obtained mixture
was triturated until complete crystallization, the resulting sus-
pension was left overnight at room temperature, and cooled to 0 ꢀC.
The precipitate was filtered, washed with ice-cold water and pe-
troleum ether, and dried to give 17j (3.465 g, 95%). Mp 140e143 ꢀC
54.72 (CHN), 14.39 (CH3 in OEt); IR (Nujol)
NH), 3063 (w) ( CHarom), 1693 (s), 1662 (m) (amide-I and
Bz), 1612 (w), 1594 (m) ( CCarom), 1509 (s) (amide-II), 1278 (s), 1035
(s) ( CeO), 835 (m), 690 (m) ( CHarom). Anal. Calcd for C26H25NO5:
n
, cmꢁ1: 3365 (m) (
C]O in
n
n
n
n
n
d
C, 72.37; H, 5.84; N, 3.25. Found: C, 72.46; H, 5.72; N, 3.22.
4.3.13. Ethyl N-{[2-benzoyl-1-(4-tert-butylphenyl)-3-oxo-3-phenyl]
prop-1-yl}carbamate (17m). Compound 17m (2.044 g, 98%) was
prepared from dibenzoylmethane (16c) (1.072 g, 4.78 mmol), NaH
(0.109 g, 4.56 mmol) and sulfone 15d (1.774 g, 4.55 mmol) in dry
THF (21 mL) (rt, 8 h) as described for 17j. Mp 170e172 ꢀC (EtOH). 1H
(EtOH). 1H NMR (300.13 MHz, DMSO-d6)
d: 7.99e8.04 (2H, m, ArH),
7.74e7.79 (2H, m, ArH), 7.74 (1H, d, 3J¼9.1 Hz, NH, signals partly
overlap with signals of aromatic protons), 7.60e7.66 (1H, m, ArH),
7.47e7.57 (3H, m, ArH), 7.36e7.43 (4H, m, ArH), 7.15e7.22 (2H, m,
ArH), 7.05e7.12 (1H, m, ArH), 6.38 (1H, d, 3J¼10.1 Hz, CHC]O), 5.53
(1H, dd, 3J¼10.1, 3J¼9.1 Hz, CHN), 3.78e3.93 (2H, m, OCH2), 1.03
NMR (300.13 MHz, DMSO-d6) d: 7.98e8.04 (2H, m, ArH), 7.71e7.76
(2H, m, ArH), 7.69 (1H, d, 3J¼9.1 Hz, NH), 7.59e7.66 (1H, m, ArH),
7.47e7.55 (3H, m, ArH), 7.34e7.41 (2H, m, ArH), 7.25e7.30 (2H, m,
ArH), 7.15e7.20 (2H, m, ArH), 6.33 (1H, d, 3J¼10.0 Hz, CHC]O), 5.49
(1H, dd, 3J¼10.0, 3J¼9.1 Hz, CHN), 3.78e3.92 (2H, m, OCH2), 1.13
(9H, s, CH3 in t-Bu), 1.03 (3H, t, 3J¼7.1 Hz, CH3 in OEt); 13C NMR
(3H, t, 3J¼7.1 Hz, CH3); 13C NMR (75.48 MHz, DMSO-d6)
d: 193.32
(C]O in Bz),193.09 (C]O in Bz),155.18 (C]O in COOEt),140.56 (C),
136.30 (C), 135.59 (C), 133.85 (CH), 133.81 (CH), 128.95 (2CH),
128.85 (2CH), 128.61 (2CH), 128.34 (2CH), 128.10 (2CH), 127.54
(2CH), 127.25 (CH), 59.85 (OCH2), 59.75 (CHBz2), 55.22 (CHN), 14.39
(75.48 MHz, DMSO-d6) d: 193.60 (C]O in Bz), 193.31 (C]O in Bz),
155.16 (C]O in COOEt), 149.50 (C), 137.55 (C), 136.31 (C), 135.63 (C),
133.78 (CH), 133.61 (CH), 128.94 (2CH), 128.71 (2CH), 128.55 (2CH),
128.34 (2CH), 127.12 (2CH), 124.79 (2CH), 59.80 (OCH2), 59.67
(CHBz2), 54.76 (CHN), 34.04 (CMe3), 30.98 (3ꢂCH3 in t-Bu), 14.40
(CH3); IR (Nujol)
3031 (w) ( CHarom),1724 (s),1693 (s),1661 (m) (amide-I and
in Bz), 1595 (m) ( CCarom), 1527 (s) (amide-II), 1499 (w) ( CCarom),
1284 (s), 1041 (s) ( CeO), 762 (s), 699 (s) ( CHarom). Anal. Calcd for
n
, cmꢁ1: 3354 (br s), 3317 (sh) (
n
NH), 3062 (w),
n
n
C]O
(CH3 in OEt); IR (Nujol)
n
, cmꢁ1: 3367 (br m) (
n
NH), 3061 (w) (
C]O in Bz),
CCarom), 1518 (s) (amide-II), 1283 (s), 1042 (m)
CeO), 809 (m), 768 (m), 690 (m) ( CHarom). Anal. Calcd for
29H31NO4: C, 76.12; H, 6.83; N, 3.06. Found: C, 76.07; H, 6.81; N,
n
n
n
CHarom), 1722 (s), 1696 (s), 1654 (m) (amide-I and
1595 (m), 1578 (w) (
n
n
d
n
C25H23NO4: C, 74.80; H, 5.77; N, 3.49. Found: C, 74.73; H, 5.67; N,
3.64.
(n
d
C
2.94.
4.3.11. Ethyl
N-{[2-benzoyl-1-(4-methylphenyl)-3-oxo-3-phenyl]
prop-1-yl}carbamate (17k). Compound 17k (3.916 g, 96%) was
prepared from dibenzoylmethane (16c) (2.326 g, 10.17 mmol), NaH
(0.237 g, 9.88 mmol) and sulfone 15b (3.428 g, 9.87 mmol) in dry
THF (25 mL) (rt, 8 h) as described for 17j. Mp 162e163.5 ꢀC (EtOH).
4.3.14. Ethyl
N-{[2-benzoyl-1-(4-chlorophenyl)-3-oxo-3-phenyl]
prop-1-yl}carbamate (17n). Compound 17n (3.656 g, 98%) was
prepared from dibenzoylmethane (16c) (2.015 g, 8.98 mmol), NaH
(0.206 g, 8.58 mmol) and sulfone 15e (3.148 g, 8.56 mmol) in dry
THF (24 mL) (rt, 8 h) as described for 17j. Mp 160e161 ꢀC (EtOH). 1H
1H NMR (300.13 MHz, DMSO-d6)
d: 8.00e8.05 (2H, m, ArH),
7.75e7.81 (2H, m, ArH), 7.67 (1H, d, 3J¼9.2 Hz, NH), 7.47e7.66 (4H,
m, ArH), 7.37e7.44 (2H, m, ArH), 7.25e7.31 (2H, m, ArH), 6.96e7.02
(2H, m, ArH), 6.37 (1H, d, 3J¼10.1 Hz, CHC]O), 5.51 (1H, dd, 3J¼10.1,
3J¼9.2 Hz, CHN), 3.77e3.91 (2H, m, OCH2), 2.14 (3H, s, CH3 in 4-
MeC6H4), 1.02 (3H, t, 3J¼7.1 Hz, CH3); 13C NMR (75.48 MHz,
NMR (300.13 MHz, DMSO-d6) d: 8.00e8.05 (2H, m, ArH), 7.76e7.81
(2H, m, ArH), 7.76 (1H, d, 3J¼9.1 Hz, NH, signals partly overlap with
signals of aromatic protons), 7.48e7.67 (4H, m, ArH), 7.38e7.45 (4H,
m, ArH), 7.23e7.29 (2H, m, ArH), 6.38 (1H, d, 3J¼10.1 Hz, CHC]O),
5.51 (1H, dd, 3J¼10.1, 3J¼9.1 Hz, CHN), 3.78e3.92 (2H, m, OCH2),1.03
DMSO-d6)
d
: 193.23 (C]O in Bz), 193.21 (C]O in Bz), 155.14 (C]O
(3H, t, 3J¼7.1 Hz, CH3); 13C NMR (75.48 MHz, DMSO-d6)
d: 193.28
in COOEt), 137.67 (C), 136.33 (C), 136.31 (C), 135.67 (C), 133.83 (CH),
133.77 (CH), 128.92 (2CH), 128.87 (2CH), 128.65 (2CH), 128.63
(2CH), 128.34 (2CH), 127.46 (2CH), 59.87 (CHBz2), 59.80 (OCH2),
54.99 (CHN), 20.55 (CH3 in 4-MeC6H4), 14.38 (CH3 in OEt); IR
(C]O in Bz),193.00 (C]O in Bz),155.18 (C]O in COOEt),139.58 (C),
136.19 (C), 135.49 (C), 133.93 (CH), 133.92 (CH), 131.84 (C), 129.47
(2CH), 128.96 (2CH), 128.91 (2CH), 128.64 (2CH), 128.36 (2CH),
128.08 (2CH), 59.94 (OCH2), 59.55 (CHBz2), 54.63 (CHN), 14.35
(Nujol)
1682 (s) (amide-I and
1551 (s) (amide-II), 1516 (w) (
n
, cmꢁ1: 3288 (br s) (
n
NH), 3061 (w) (
C]O in Bz), 1596 (m), 1579 (w) (
CCarom), 1289 (s), 1045 (s) (
n
CHarom), 1694 (s),
CCarom),
CeO),
(CH3); IR (Nujol)
CHarom), 1694 (vs), 1660 (m) (amide-I and
1578 (w) ( CCarom), 1515 (s) (amide-II), 1490 (w) (n
n
, cmꢁ1: 3379 (br m), 3366 (sh) (
n
NH), 3062 (w) (
C]O in Bz), 1595 (m),
CCarom), 1294
n
n
n
n
n
n
n

A.A. Fesenko, A.D. Shutalev / Tetrahedron 71 (2015) 9528e9543
9537
(s), 1039 (m) (
n
CeO), 829 (m), 759 (w), 690 (m) (
d
CHarom). Anal.
CHN), 3.84e4.00 (2H, m, OCH2), 2.86 (1H, dd, 2J¼16.5, 3J¼9.1 Hz, HA
in CH2C]O), 2.73 (1H, dd, 2J¼16.5, 3J¼5.6 Hz, HB in CH2C]O), 2.25
(3H, s, CH3 in 4-MeC6H4), 2.06 (3H, s, CH3 in Ac), 1.12 (3H, t,
Calcd for C25H22ClNO4: C, 68.89; H, 5.09; N, 3.21. Found: C, 68.84; H,
5.05; N, 3.28.
3J¼7.1 Hz, CH3 in OEt); 13C NMR (75.48 MHz, DMSO-d6)
d: 205.83
4.3.15. Ethyl
N-[(2-benzoyl-1-oxo-1-phenyl)hex-3-yl]carbamate
(C]O in Ac), 155.46 (C]O in COOEt), 140.37 (C), 135.89 (C), 127.80
(2CH), 126.21 (2CH), 59.63 (OCH2), 50.25 (CHN), 49.54 (CH2C]O),
30.08 (CH3 in Ac), 20.63 (CH3 in 4-MeC6H4), 14.59 (CH3 in OEt); IR
(17o). Compound 17o (3.381 g, 95%) was prepared from diben-
zoylmethane (16c) (2.282 g, 10.17 mmol), NaH (0.233 g, 9.70 mmol)
and sulfone 15f (2.903 g, 9.70 mmol) in dry THF (25 mL) (rt, 8 h) as
described for 17j. Mp 131e132 ꢀC (EtOH). 1H NMR (300.13 MHz,
(Nujol)
C]O in Ac), 1690 (vs) (amide-I), 1546 (s) (amide-II), 1268 (s), 1160
(m) ( CeO), 804 (m) ( CHarom). Anal. Calcd for C14H19NO3: C, 67.45;
H, 7.68; N, 5.62. Found: C, 67.44; H, 7.70; N, 5.69.
n n NH), 3051 (w) (n CHarom), 1714 (s) (n
, cmꢁ1: 3318 (vs) (
DMSO-d6)
d
: 7.94e8.01 (4H, m, ArH), 7.60e7.68 (2H, m, ArH),
n
d
7.48e7.57 (4H, m, ArH), 6.92 (1H, d, 3J¼9.1 Hz, NH), 5.96 (1H, d,
3J¼7.6 Hz, CHC]O), 4.34 (1H, dddd, 3J¼10.6, 3J¼9.1, 3J¼7.6,
3J¼3.0 Hz, CHN), 3.75e3.90 (2H, m, OCH2), 1.13e1.66 (4H, m,
CH2CH2CH3), 0.99 (3H, t, 3J¼7.1 Hz, CH3 in OEt), 0.81 (3H, t,
4.4.3. Ethyl
N-{[1-(4-methoxylphenyl)-3-oxo]but-1-yl}carbamate
(18c). Compound 18c (2.007 g, 92%, pale yellow solid) was pre-
pared from carbamate 17c (2.521 g, 8.20 mmol) and KOH (2.355 g,
41.96 mmol) in H2O (41 mL) (rt, 3 h) as described for 18a. An an-
alytically pure sample (0.246 g, white solid) was obtained from
crude 18c (0.353 g) using column chromatography on silica gel 60
(10 g) eluting with petroleum ethereCHCl3 (from 4:1 to 1.5:1). After
the removal of solvent the residue was dissolved in CHCl3 (about
1 mL), hexane (about 2 mL) was added until crystallization began.
Obtained solid was filtered, washed with hexane and dried under
high vacuum (0.1 mmHg). Mp 101.5e102.5 ꢀC (CHCl3ehexane, 1:2).
3J¼7.1 Hz, CH3 in Pr); 13C NMR (75.48 MHz, DMSO-d6)
d: 195.08 (C]
O in Bz), 194.72 (C]O in Bz), 155.68 (C]O in COOEt), 136.33 (C),
136.12 (C), 133.85 (CH), 133.65 (CH), 128.09 (2CH), 128.89 (2CH),
128.49 (2CH), 128.37 (2CH), 59.53 (OCH2), 58.96 (CHBz2), 51.27
(CHN), 34.65 (CH2CH2CH3), 18.99 (CH2CH2CH3), 14.44 (CH3 in OEt),
13.53 (CH3 in Pr); IR (Nujol)
(w) ( CHarom), 1699 (br s) (amide-I and
1579 (w) ( CCarom), 1545 (s) (amide-II), 1270 (s) (
691 (m) ( CHarom). Anal. Calcd for C22H25NO4: C, 71.91; H, 6.86; N,
3.81. Found: C, 71.96; H, 6.84; N, 3.91.
n
, cmꢁ1: 3350 (s) (
C]O in Bz), 1597 (w),
CeO), 766 (m),
n NH), 3108 (w), 3064
n
n
n
n
d
1H NMR (300.13 MHz, DMSO-d6)
d
: 7.59 (1H, d, 3J¼8.4 Hz, NH),
7.18e7.24 (2H, m, ArH), 6.83e6.89 (2H, m, ArH), 4.90 (1H, ddd,
3J¼9.0, 3J¼8.4, 3J¼5.8 Hz, CHN), 3.85e4.00 (2H, m, OCH2), 3.71 (3H,
s, OCH3), 2.86 (1H, dd, 2J¼16.5, 3J¼9.0 Hz, HA in CH2C]O), 2.74 (1H,
dd, 2J¼16.5, 3J¼5.8 Hz, HB in CH2C]O), 2.06 (3H, s, CH3 in Ac), 1.12
4.4. Synthesis of ethyl N-(g-oxoalkyl)carbamates
4.4.1. Ethyl N-[(3-oxo-1-phenyl)but-1-yl]carbamate (18a). To a so-
lution of KOH (5.269 g, 93.91 mmol) in H2O (90 mL) was added
carbamate 17a (5.150 g, 18.57 mmol) and the obtained mixture was
stirred at room temperature. An emulsion formed at the beginning
of stirring, and after about 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 sus-
pension was cooled to 0 ꢀC. The precipitate was filtered, washed
with ice-cold H2O and petroleum ether, and dried to give compound
18a (3.644 g, 83%). Mp 52.5e56.5 ꢀC (EtOHeH2O, 1:3).27 1H NMR
(3H, t, 3J¼7.1 Hz, CH3 in OEt); 13C NMR (75.48 MHz, DMSO-d6)
d:
205.87 (C]O in Ac), 158.12 (C), 155.41 (C]O in COOEt), 135.30 (C),
127.43 (2CH), 113.59 (2CH), 59.60 (OCH2), 55.02 (OCH3), 49.95
(CHN), 49.60 (CH2C]O), 30.07 (CH3 in Ac), 14.57 (CH3 in OEt); IR
(Nujol)
(amide-I), 1612 (w), 1584 (w) (
(m) ( CCarom), 1268 (s), 1061 (s) (
n
, cmꢁ1: 3349 (s) (
n
NH), 1715 (s) (
CCarom), 1536 (s) (amide-II), 1518
CeO), 812 (m) ( CHarom). Anal.
n C]O in Ac), 1684 (s)
n
n
n
d
Calcd for C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.48; H,
7.13; N, 5.44.
4.4.4. Ethyl N-{[1-(4-methoxyphenyl)-2-methyl-3-oxo]but-1-yl}car-
bamate (18e). To a solution of KOH (1.533 g, 27.31 mmol) in H2O
(27 mL) was added carbamate 17h (2.925 g, 9.10 mmol), the ob-
tained suspension was stirred at room temperature for 1 h 50 min
and cooled to 0 ꢀC. The precipitate was filtered, washed with ice-
cold H2O and petroleum ether, and dried to give compound 18e
(1.886 g, 74%) as a mixture of two diastereomers (51:49). An ana-
lytically pure sample (0.295 g; a 54:46 diastereomeric mixture) was
obtained from crude 18e (0.357 g) using column chromatography on
silica gel 60 (9 g) eluting with petroleum ethereCHCl3 (from 5:1 to
2:1). After the removal of solvent the residue was triturated with
hexane until complete crystallization, obtained solid was filtered,
washed with hexane and dried under high vacuum (0.1 mmHg). Mp
77.5e79.5 ꢀC. 1H NMR of the major isomer (300.13 MHz, DMSO-d6)
(300.13 MHz, DMSO-d6)
d
: 7.64 (1H, d, 3J¼8.2 Hz, NH), 7.18e7.35 (5H,
m, ArH), 4.95 (1H, ddd, 3J¼9.2, 3J¼8.2, 3J¼5.5 Hz, CHN), 3.85e4.01
(2H, m, OCH2), 2.88 (1H, dd, 2J¼16.6, 3J¼9.2 Hz, HA in CH2C]O), 2.76
(1H, dd, 2J¼16.6, 3J¼5.5 Hz, HB in CH2C]O), 2.07 (3H, s, CH3 in Ac),
1.13 (3H, t, 3J¼7.1 Hz, CH3 in OEt); 13C NMR (75.48 MHz, DMSO-d6)
d:
205.68 (C]O in Ac), 155.45 (C]O in COOEt), 143.34 (C),
128.22(2CH), 126.79 (CH), 126.22 (2CH), 59.62 (OCH2), 50.47 (CHN),
49.47 (CH2C]O), 30.01 (CH3 in Ac), 14.53 (CH3 in OEt); IR (Nujol)
cmꢁ1: 3329 (vs) (
NH), 3064 (w), 3029 (w) ( CHarom), 1713 (s) (
C]O in Ac), 1688 (vs) (amide-I), 1603 (w), 1582 (w) ( CCarom), 1545
(vs) (amide-II), 1496 (w) ( CCarom), 1265 (vs), 1158 (s) ( CeO), 758
(s), 705 (s) ( CHarom). Anal. Calcd for C13H17NO3: C, 66.36; H, 7.28; N,
5.95. Found: C, 66.38; H, 7.29; N, 6.02.
n,
n
n
n
n
n
n
d
d
: 7.65 (1H, d, 3J¼9.8 Hz, NH), 7.17e7.23 (2H, m, ArH, signals partly
overlap with signals of analogous protons of the minor isomer),
6.82e6.88 (2H, m, ArH, signals partly overlap with signals of anal-
ogous protons of the minor isomer), 4.76 (1H, dd, 3J¼9.8, 3J¼8.8 Hz,
CHN), 3.87e4.02 (2H, m, OCH2, signals partly overlap with signals of
analogous protons of the minor isomer), 3.71 (3H, s, OCH3), 2.98 (1H,
dq, 3J¼8.8, 3J¼6.9 Hz, CHAc), 1.91 (3H, s, CH3 in Ac), 1.13 (3H, t,
3J¼7.1 Hz, CH3 in OEt), 0.98 (3H, d, 3J¼6.9 Hz, CH3CH); 1H NMR of the
4.4.2. Ethyl
N-{[1-(4-methylphenyl)-3-oxo]but-1-yl}carbamate
(18b). Compound 18b (2.972 g, 91%) was prepared from carbamate
17b (3.597 g, 12.35 mmol) and KOH (3.550 g, 63.24 mmol) in H2O
(60 mL) (rt, 3 h) as described for 18a. An analytically pure sample
(0.285 g) was obtained from crude 18b (0.362 g) using column
chromatography on silica gel 60 (6 g) eluting with petroleum
ethereCHCl3 (from 3:1 to 1:2). After the removal of solvent the
residue was triturated with hexane until complete crystallization,
obtained solid was filtered, washed with hexane, and dried under
high vacuum (0.1 mmHg). Mp 57e58 ꢀC. 1H NMR (300.13 MHz,
minor isomer (300.13 MHz, DMSO-d6)
d
: 7.69 (1H, d, 3J¼9.2 Hz, NH),
7.20e7.26 (2H, m, ArH, signals partly overlap with signals of anal-
ogous protons of the major isomer), 6.85e6.91 (2H, m, ArH, signals
partly overlap with signals of analogous protons of the major iso-
mer), 4.55 (1H, dd, 3J¼10.6, 3J¼9.2 Hz, CHN), 3.81e3.96 (2H, m,
OCH2, signals partly overlap with signals of analogous protons of the
DMSO-d6)
d
: 7.61 (1H, d, 3J¼8.4 Hz, NH), 7.14e7.19 (2H, m, ArH),
7.07e7.12 (2H, m, ArH), 4.91 (1H, ddd, 3J¼9.1, 3J¼8.4, 3J¼5.6 Hz,

9538
A.A. Fesenko, A.D. Shutalev / Tetrahedron 71 (2015) 9528e9543
major isomer), 3.73 (3H, s, OCH3), 2.86 (1H, dq, 3J¼10.6, 3J¼7.1 Hz,
CHAc), 2.17 (3H, s, CH3 in Ac),1.09 (3H, t, 3J¼7.1 Hz, CH3 in OEt), 0.69
(3H, d, 3J¼7.1 Hz, CH3CH); 13C NMR of the major isomer (75.48 MHz,
prepared from carbamate 17n (2.849 g, 6.54 mmol) and KOH
(1.214 g, 21.64 mmol) in EtOH (9 mL) and H2O (17 mL for reaction,
17 mL for dilution after completion of the reaction) (rt, 8 h) as
described for 18f. Mp 159e161 ꢀC (EtOH). 1H NMR (300.13 MHz,
DMSO-d6) d: 209.87 (C]O in Ac),158.13 (C),155.87 (C]O in COOEt),
133.98 (C), 128.04 (2CH), 113.52 (2CH), 59.75 (OCH2), 55.59 (CHN),
54.98 (OCH3), 51.71 (CHAc), 29.25 (CH3 in Ac), 14.49 (CH3 in OEt),
12.88 (CH3CHAc); 13C NMR of the minor isomer (75.48 MHz, DMSO-
d6) d: 210.74 (C]O in Ac),158.28 (C),155.26 (C]O in COOEt),133.55
(C), 128.36 (2CH), 113.58 (2CH), 59.63 (OCH2), 54.44 (CHN), 54.98
DMSO-d6)
d
: 7.91e7.96 (2H, m, ArH), 7.63 (1H, d, 3J¼8.3 Hz, NH,
signals overlap with signals of aromatic proton), 7.60e7.66 (1H, m,
ArH), 7.48e7.55 (2H, m, ArH), 7.24e7.30 (2H, m, ArH), 6.84e6.90
(2H, m, ArH), 5.09 (1H, ddd, 3J¼8.9, 3J¼8.3, 3J¼5.3 Hz, CHN),
3.84e3.99 (2H, m, OCH2), 3.72 (3H, s, OCH3), 3.55 (1H, dd, 2J¼16.9,
3J¼8.9 Hz, HA in CH2C]O), 3.27 (1H, dd, 2J¼16.9, 3J¼5.3 Hz, HB in
CH2C]O), 1.11 (3H, t, 3J¼7.1 Hz, CH3 in OEt); 13C NMR (75.48 MHz,
(OCH3), 51.13 (CHAc), 28.78 (CH3 in Ac), 14.56 (CH3 in OEt), 12.88
(CH3CHAc); IR (Nujol)
C]O in Ac), 1685 (s) (amide-I), 1615 (w), 1584 (w) (
(s) (amide-II),1517 (m) ( CCarom),1264 (s),1031 (s) (
CHarom). Anal. Calcd for C15H21NO4: C, 64.50; H, 7.58; N, 5.01.
Found: C, 64.69; H, 7.57; N, 5.26.
n
, cmꢁ1: 3353 (s) (
n
NH), 1712 (s), 1702 (m) (
CCarom), 1535
CeO), 832 (m)
n
n
n
DMSO-d6) d: 197.22 (C]O in Bz), 158.15 (C), 155.41 (C]O in COOEt),
n
136.67 (C), 135.42 (C), 133.22 (CH), 128.72 (2CH), 127.99 (2CH),
127.59 (2CH), 113.60 (2CH), 59.57 (OCH2), 55.03 (OCH3), 50.23
(d
(CHN), 44.79 (CH2C]O),14.57 (CH3 in OEt); IR (Nujol)
(s) ( NH), 3061 (w) ( CHarom), 1691 (s) (amide-I and C]O in Bz),
1597 (w), 1578 (w) ( CCarom), 1547 (s) (amide-II), 1491 (w) (
CCarom), 1264 (s), 1048 (s) ( CeO), 824 (m), 759 (m), 691 (m) (
n
, cmꢁ1: 3316
n
n
4.4.5. Ethyl N-[(3-oxo-1,3-diphenyl)prop-1-yl]carbamate (18f). To
a cooled (10 ꢀC) solution of KOH (1.765 g, 31.45 mmol) in H2O
(26 mL) were added carbamate 17j (4.200 g, 10.46 mmol) and EtOH
(15.5 mL), the obtained suspension was stirred at room temperature
for 8 h. Then H2O (26 mL) was added, the resulting suspension was
cooled to 0 ꢀC. The precipitate was filtered, washed with ice-cold
H2O and petroleum ether, and dried to give compound 18f
(2.158 g, 69%, pale yellow solid). Mp 96.5e97.5 ꢀC (EtOHeH2O, 2:1)
n
n
n
d
CHarom). Anal. Calcd for C18H18ClNO3: C, 65.16; H, 5.47; N, 4.22.
Found: C, 65.21; H, 5.40; N, 4.20.
4.4.8. Ethyl
N-{[1-(4-methoxyphenyl)-3-oxo-3-phenyl]prop-1-yl}
carbamate (18i). Compound 18i (1.725 g, 66%, pale yellow solid)
was prepared from carbamate 17l (3.457 g, 8.01 mmol) and KOH
(1.337 g, 23.89 mmol) in EtOH (12.2 mL) and H2O (20 mL for re-
action, 20 mL for dilution after completion of the reaction) (rt, 9 h)
as described for 18f. Mp 159e161 ꢀC (EtOH). 1H NMR (300.13 MHz,
(lit.28 mp 98e99 ꢀC). 1H NMR (300.13 MHz, DMSO-d6)
d: 7.91e7.97
(2H, m, ArH), 7.70 (1H, d, 3J¼8.2 Hz, NH), 7.60e7.67 (1H, m, ArH),
7.48e7.56 (2H, m, ArH), 7.28e7.39 (4H, m, ArH), 7.19e7.26 (1H, m,
ArH), 5.15 (1H, ddd, 3J¼9.2, 3J¼8.2, 3J¼4.9 Hz, CHN), 3.85e4.00 (2H,
m, OCH2), 3.58 (1H, dd, 2J¼17.1, 3J¼9.2 Hz, HA in CH2C]O), 3.29 (1H,
DMSO-d6)
d
: 7.91e7.96 (2H, m, ArH), 7.63 (1H, d, 3J¼8.3 Hz, NH,
signals overlap with signals of aromatic proton), 7.60e7.66 (1H, m,
ArH), 7.48e7.55 (2H, m, ArH), 7.24e7.30 (2H, m, ArH), 6.84e6.90
(2H, m, ArH), 5.09 (1H, ddd, 3J¼8.9, 3J¼8.3, 3J¼5.3 Hz, CHN),
3.84e3.99 (2H, m, OCH2), 3.72 (3H, s, OCH3), 3.55 (1H, dd, 2J¼16.9,
3J¼8.9 Hz, HA in CH2C]O), 3.27 (1H, dd, 2J¼16.9, 3J¼5.3 Hz, HB in
CH2C]O), 1.11 (3H, t, 3J¼7.1 Hz, CH3 in OEt); 13C NMR (75.48 MHz,
dd, 2J¼17.1, 3J¼4.9 Hz, HB in CH2C]O),1.11 (3H, t, 3J¼7.1 Hz, CH3); 13
C
NMR (75.48 MHz, DMSO-d6) d: 197.09 (C]O in Bz), 155.49 (C]O in
COOEt), 143.52 (C), 136.63 (C), 133.26 (CH), 128.73 (2CH), 128.29
(2CH), 128.02 (2CH), 126.87 (CH), 126.44 (2CH), 59.64 (OCH2), 50.75
(CHN), 44.73 (CH2C]O), 14.57 (CH3); IR (Nujol)
NH), 3085 (w), 3066 (w), 3056 (w), 3028 (w), 3004 (w) (
1717 (s) (amide-I), 1679 (s) (C]O in Bz), 1596 (w), 1579 (w) (
CCarom), 1525 (s) (amide-II), 1494 (w) ( CCarom), 1294 (s), 1038 (s) (
CeO), 769 (m), 705 (s) (
n
, cmꢁ1: 3377 (s) (
CHarom),
n
n
DMSO-d6) d: 197.22 (C]O in Bz), 158.15 (C), 155.41 (C]O in COOEt),
n
n
136.67 (C), 135.42 (C), 133.22 (CH), 128.72 (2CH), 127.99 (2CH),
127.59 (2CH), 113.60 (2CH), 59.57 (OCH2), 55.03 (OCH3), 50.23
n
d
CHarom). Anal. Calcd for C18H19NO3: C,
(CHN), 44.79 (CH2C]O), 14.57 (CH3 in OEt); IR (Nujol)
3304 (s) ( NH), 3069 (w), 3023 (w) ( CHarom), 1703 (s), 1691 (s),
1681 (s) (amide-I and C]O in Bz), 1610 (w), 1595 (w), 1578 (w) (
CCarom), 1551 (s) (amide-II), 1513 (s) ( CCarom), 1276 (s), 1049 (s) (
CeO), 830 (m), 765 (m), 691 (m) (
19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found: C, 69.76; H, 6.48; N,
n :
, cmꢁ1
72.71; H, 6.44; N, 4.71. Found: C, 72.80; H, 6.45; N, 4.72.
n
n
n
n
4.4.6. Ethyl N-{[1-(4-methylphenyl)-3-oxo-3-phenyl]prop-1-yl}car-
bamate (18g). Compound 18g (1.707 g, 67%, pale yellow solid) was
prepared from carbamate 17k (3.415 g, 8.22 mmol) and KOH
(1.383 g, 24.64 mmol) in EtOH (15 mL) and H2O (25 mL for reaction,
25 mL for dilution after completion of the reaction) (rt, 9 h 20 min)
as described for 18f. Mp 105e108 ꢀC (EtOH). 1H NMR (300.13 MHz,
n
d
CHarom). Anal. Calcd for
C
4.31.
4.5. Synthesis of 4-(
g
-oxoalkyl)semicarbazide hydrazones
DMSO-d6)
d
: 7.90e7.96 (2H, m, ArH), 7.65 (1H, d, 3J¼8.2 Hz, NH,
signals overlap with signals of aromatic proton), 7.60e7.67 (1H, m,
ArH), 7.48e7.55 (2H, m, ArH), 7.21e7.26 (2H, m, ArH), 7.08e7.14
(2H, m, ArH), 5.10 (1H, ddd, 3J¼9.1, 3J¼8.2, 3J¼5.2 Hz, CHN),
3.84e3.99 (2H, m, OCH2), 3.56 (1H, dd, 2J¼17.0, 3J¼9.1 Hz, HA in
CH2C]O), 3.27 (1H, dd, 2J¼17.0, 3J¼5.2 Hz, HB in CH2C]O), 2.26
(3H, s, CH3 in 4-MeC6H4), 1.11 (3H, t, 3J¼7.1 Hz, CH3 in OEt); 13C NMR
4.5.1. Hydrazone
of
4-[(3-oxo-1-phenyl)but-1-yl]semicarbazide
(20a). To carbamate 18a (2.691 g, 11.44 mmol) was added anhy-
drous N2H4 (25 mL), the flask was flushed with argon, and the
resulting solution was refluxed under stirring for 23 h with pro-
tection from air moisture and CO2 using a KOH pellets filled tube.
After completion of the reaction, N2H4 was removed in vacuo at
about 60 ꢀC (bath temperature), the oily residue was co-evaporated
4e6 times with toluene until white solid was formed. The obtained
solid was triturated with Et2O (15 mL) and the resulting suspension
was cooled (ꢁ18 ꢀC). The precipitate was filtered, washed with cold
(ꢁ18 ꢀC) diethyl ether, dried on the filter by sucking air through the
filter. The powder product was washed on the filter with ice-cold
water (4ꢂ5 mL), petroleum ether, and dried to give 20a (0.957 g,
36%) as a mixture of (E)- and (Z)-isomers in a ratio of 84:16. An
analytically pure sample (a 85:15 isomeric ratio) was obtained after
two crystallizations from MeCN. Mp 130e134 ꢀC (dec, MeCN). 1H
(75.48 MHz, DMSO-d6) d: 197.15 (C]O in Bz), 155.42 (C]O in
COOEt), 140.47 (C), 136.65 (C), 135.90 (C), 133.22 (CH), 128.79 (2CH),
128.72 (2CH), 127.99 (2CH), 126.36 (2CH), 59.58 (OCH2), 50.50
(CHN), 44.72 (CH2C]O), 20.63 (CH3 in 4-MeC6H4), 14.56 (CH3 in
OEt); IR (Nujol)
(w), 3022 (w) (
n
n
, cmꢁ1: 3319 (s) (
CHarom), 1706 (s), 1694 (s), 1685 (s) (amide-I and
n
NH), 3062 (w), 3052 (w), 3038
C]O in Bz), 1595 (w), 1578 (w) (
n
CCarom), 1546 (s) (amide-II), 1512
(w) ( CCarom), 1273 (s), 1051 (s) (
n
n
CeO), 814 (w), 761 (m), 691 (m)
(d CHarom). Anal. Calcd for C19H21NO3: C, 73.29; H, 6.80; N, 4.50.
Found: C, 73.29; H, 7.03; N, 4.32.
NMR of the major isomer (300.13 MHz, DMSO-d6) d: 7.15e7.40 (5H,
4.4.7. Ethyl N-{[1-(4-chlorophenyl)-2-methyl-3-oxo]but-1-yl}carba-
mate (18h). Compound 18h (1.808 g, 83%, pale yellow solid) was
m, ArH, signals overlap with signals of aromatic protons of the
minor isomer), 6.98 (1H, br s, NHNH2), 6.68 (1H, br d, 3J¼8.4 Hz,

A.A. Fesenko, A.D. Shutalev / Tetrahedron 71 (2015) 9528e9543
9539
NHCH), 5.59 (2H, br s, NH2N]C), 4.89 (1H, ddd, 3J¼8.5, 3J¼8.4,
3J¼6.2 Hz, CHN), 4.11 (2H, br s, NH2NH), 2.50 (1H, dd, 2J¼14.0,
3J¼6.2 Hz, HA in CH2C]N), 2.46 (1H, dd, 2J¼14.0, 3J¼8.5 Hz, HB in
CH2C]N), 1.59 (3H, s, CH3C]N); 1H NMR of the minor isomer
d6) d: 7.26e7.31 (2H, m, ArH), 7.00 (1H, br s, NHNH2), 6.85e6.90
(2H, m, ArH, signals partly overlap with signals of analogous pro-
tons of the major isomer), 6.70 (1H, br d, 3J¼8.8 Hz, NHCH), 5.70
(2H, br s, NH2N]C), 4.91 (1H, ddd, 3J¼8.8, 3J¼8.7, 3J¼6.9 Hz, CHN),
z4.07 (2H, br s, NH2NH, signal fully overlap with signal of analo-
gous protons of the major isomer), 3.73 (3H, s, OCH3), 2.77 (1H, dd,
2J¼14.2, 3J¼8.7 Hz, HA in CH2C]N), 2.32 (1H, dd, 2J¼14.2, 3J¼6.9 Hz,
HB in CH2C]N), 1.63 (3H, s, CH3C]N); 13C NMR of the major isomer
(300.13 MHz, DMSO-d6) d: 7.15e7.40 (5H, m, ArH, signals overlap
with signals of aromatic protons of the major isomer), 7.04 (1H, br s,
NHNH2), 6.81 (1H, br d, 3J¼8.5 Hz, NHCH), 5.71 (2H, br s, NH2N]C),
4.98 (1H, ddd, 3J¼9.3, 3J¼8.5, 3J¼6.3 Hz, CHN), 4.11 (2H, br s,
NH2NH, signal fully overlap with signal of analogous protons of the
major isomer), 2.80 (1H, dd, 2J¼14.4, 3J¼9.3 Hz, HA in CH2C]N),
2.32 (1H, dd, 2J¼14.4, 3J¼6.3 Hz, HB in CH2C]N), 1.66 (3H, s, CH3C]
(75.48 MHz, DMSO-d6)
136.53 (C), 127.36 (2CH), 113.43 (2CH), 55.00 (OCH3), 50.55 (CHN),
45.87 (CH2), 13.89 (CH3C]N); IR (Nujol)
, cmꢁ1: 3392 (s), 3341 (s),
3325 (m), 3222 (br s) ( NH), 3100 (w), 3061 (br m), 3034 (w) (
CHarom), 1656 (s), 1639 (s) (amide-I, C]N, NH2), 1615 (m), 1584
(w) ( CCarom), 1528 (s) (amide-II), 1513 (s) ( CCarom), 1252 (s), 1034
(m) ( CeO), 824 (m) ( CHarom). Anal. Calcd for C12H19N5O2: C,
d: 159.36 (C]O), 157.84 (C), 144.68 (C]N),
n
N); 13C NMR of the major isomer (75.48 MHz, DMSO-d6)
d
: 159.40
n
n
(C]O), 144.66, 144.56 (C]N, C-1 in Ph), 128.08 (2CH), 126.41 (CH),
n
d
126.24 (2CH), 51.16 (CHN), 45.86 (CH2), 13.92 (CH3); 13C NMR of the
n
n
minor isomer (75.48 MHz, DMSO-d6)
144.20 (C]N, C-1 in Ph), 128.21 (2CH), 126.78 (CH), 126.41 (2CH),
49.92 (CHN), 35.92 (CH2), 22.90 (CH3); IR (Nujol)
, cmꢁ1: 3395 (s),
3346 (s), 3224 (br s), 3061 (m) ( NH), 3028 (w) ( CHarom), 1656 (br
vs) (amide-I, C]N, NH2), 1579 (w) ( CCarom), 1528 (vs) (amide-
II), 1495 (w) ( CCarom), 757 (m), 700 (s) ( CHarom). Anal. Calcd for
11H17N5O: C, 56.15; H, 7.28; N, 29.77. Found: C, 56.31; H, 7.32; N,
29.64.
d: 159.54 (C]O), 144.89,
n
d
54.33; H, 7.22; N, 26.40. Found: C, 54.51; H, 7.21; N, 26.41.
n
n
n
4.5.4. Hydrazone of 4-{[1-(4-tert-butylphenyl)-3-oxo]but-1-yl}semi-
carbazide (20d). To a solution of KOH (1.476 g, 26.30 mmol) in H2O
(25 mL) was added carbamate 17d (1.698 g, 5.09 mmol), the ob-
tained emulsion was stirred at room temperature for 4 h and
extracted with diethyl ether (20 mL, 3ꢂ10 mL). The combined ex-
tracts were washed with H2O (3ꢂ15 mL), brine (2ꢂ15 mL), and
dried over Na2SO4. Ether was removed in vacuo to give crude oily
18d.29 To the obtained residue was added anhydrous N2H4 (24 mL),
the flask was flushed with argon, the resulting solution was
refluxed under stirring for 22 h with the protection from air
moisture and CO2 using a KOH pellets filled tube. Then N2H4 was
removed in vacuo at about 60 ꢀC (bath temperature), the oily res-
idue was co-evaporated with toluene (4ꢂ15 mL). The obtained
semisolid was triturated with Et2O (15 mL) and the resulting sus-
pension was cooled (ꢁ18 ꢀC). The precipitate was filtered, washed
with cold (ꢁ18 ꢀC) diethyl ether, dried on the filter by sucking air
through the filter. The powder product was washed on the filter
with ice-cold water (4ꢂ5 mL), petroleum ether, and dried to give
20d (0.619 g, 42%) as a mixture of (E)- and (Z)-isomers in a ratio of
94:6. An analytically pure sample (a 94:6 isomeric ratio) was ob-
tained after crystallization from MeCN. Mp 151.5e152.5 ꢀC (dec,
n
d
n
n
d
C
4.5.2. Hydrazone of 4-{[1-(4-methylphenyl)-3-oxo]but-1-yl}semi-
carbazide (20b). Hydrazone 20b (0.645 g, 41%) as a mixture of (E)-
and (Z)-isomers in a ratio of 90:10 was prepared from carbamate
18b (1.585 g, 6.36 mmol) in dry N2H4 (11 mL) (reflux, 20 h) as de-
scribed for 20a. An analytically pure sample (a 96:4 mixture of
isomers) was obtained after two crystallizations from MeCN. Mp
145e146.5 ꢀC (dec, MeCN). 1H NMR of the major isomer
(300.13 MHz, DMSO-d6) d: 7.14e7.19 (2H, m, ArH), 7.06e7.11 (2H, m,
ArH), 6.93 (1H, br s, NHNH2), 6.60 (1H, br d, 3J¼8.4 Hz, NHCH), 5.55
(2H, br s, NH2N]C), 4.86 (1H, ddd, 3J¼8.4, 3J¼8.2, 3J¼6.5 Hz, CHN),
4.07 (2H, br s, NH2NH), 2.48 (1H, dd, 2J¼13.9, 3J¼6.5 Hz, HA in
CH2C]N), 2.44 (1H, dd, 2J¼13.9, 3J¼8.2 Hz, HB in CH2C]N), 2.26
(3H, s, CH3 in 4-MeC6H4), 1.59 (3H, s, CH3C]N); 1H NMR of the
minor isomer (300.13 MHz, DMSO-d6) d: 7.22e7.27 (2H, m, ArH),
7.06e7.19 (2H, m, ArH, signals fully overlap with signals of aromatic
protons of the major isomer), 6.99 (1H, br s, NHNH2), 6.71 (1H, br d,
3J¼8.7 Hz, NHCH), 5.69 (2H, br s, NH2N]C), 4.93 (1H, ddd, 3J¼8.8,
3J¼8.7, 3J¼6.6 Hz, CHN), z4.07 (2H, br s, NH2NH, signal fully
overlaps with signal of analogous protons of the major isomer),
2.77 (1H, dd, 2J¼14.2, 3J¼8.8 Hz, HA in CH2C]N), 2.32 (1H, dd,
2J¼14.2, 3J¼6.6 Hz, HB in CH2C]N), 2.27 (3H, s, CH3 in 4-MeC6H4),
1.64 (3H, s, CH3C]N); 13C NMR of the major isomer (75.48 MHz,
MeCN). 1H NMR of the major isomer (300.13 MHz, DMSO-d6)
d:
7.27e7.33 (2H, m, ArH), 7.17e7.23 (2H, m, ArH), 6.94 (1H, br s,
NHNH2), 6.60 (1H, br d, 3J¼8.4 Hz, NHCH), 5.58 (2H, br s, NH2N]C),
4.86 (1H, ddd, 3J¼8.7, 3J¼8.4, 3J¼6.1 Hz, CHN), 4.08 (2H, br s,
NH2NH), 2.49 (1H, dd, 2J¼14.0, 3J¼6.1 Hz, HA in CH2C]N), 2.44 (1H,
dd, 2J¼14.0, 3J¼8.7 Hz, HB in CH2C]N), 1.61 (3H, s, CH3C]N), 1.26
(9H, s, CH3 in t-Bu). 1H NMR of the minor isomer (300.13 MHz,
DMSO-d6)
128.58 (2CH), 126.12 (2CH), 50.85 (CHN), 45.84 (CH2), 20.60 (CH3 in
4-MeC6H4), 13.85 (CH3C]N); IR (Nujol)
, cmꢁ1: 3392 (s), 3348 (s),
3227 (br s), 3064 (m) ( NH), 3017 (w) ( CHarom), 1655 (br vs)
(amide-I, C]N, NH2), 1527 (vs) (amide-II), 812 (s) ( CHarom).
d: 159.34 (C]O), 144.61 (C]N), 141.51 (C), 135.31 (C),
DMSO-d6)
d
: 7.00 (1H, br s, NHNH2), 6.74 (1H, br d, 3J¼8.8 Hz,
NHCH), 5.70 (2H, br s, NH2N]C), 4.94 (1H, ddd, 3J¼9.4, 3J¼8.8,
3J¼6.2 Hz, CHN), z4.08 (2H, br s, NH2NH, signal fully overlap with
signal of analogous protons of the major isomer), 2.78 (1H, dd,
2J¼14.4, 3J¼9.4 Hz, HA in CH2C]N), 2.31 (1H, dd, 2J¼14.4, 3J¼6.2 Hz,
HB in CH2C]N), 1.67 (3H, s, CH3C]N), 1.27 (9H, s, CH3 in t-Bu).
Signals of aromatic protons fully overlap with signals of aromatic
protons of the major isomer; 13C NMR of the major isomer
n
n
n
n
d
d
Anal. Calcd for C12H19N5O: C, 57.81; H, 7.68; N, 28.09. Found: C,
57.81; H, 7.69; N, 27.81.
4.5.3. Hydrazone of 4-{[1-(4-methoxyphenyl)-3-oxo]but-1-yl}semi-
carbazide (20c). Hydrazone 20c (0.586 g, 29%) as a mixture of (E)-
and (Z)-isomers in a ratio of 92:8 was prepared from carbamate 18c
(1.988 g, 7.55 mmol) in N2H4 (16 mL) (reflux, 24 h) as described for
20a. An analytically pure sample (a 96:4 mixture of isomers) was
obtained after crystallization from MeCN. Mp 132.5e136.5 ꢀC (dec,
(75.48 MHz, DMSO-d6)
141.64 (C), 125.91 (2CH), 124.80 (2CH), 50.73 (CHN), 45.79 (CH2),
34.11 (CMe3), 31.21 (3ꢂCH3 in t-Bu), 13.83 (CH3C]N); IR (Nujol)
cmꢁ1: 3389 (m), 3349 (s), 3225 (br s) (
NH), 3058 (br m) ( CHarom),
1655 (vs) (amide-I, C]N, NH2), 1528 (vs) (amide-II), 823 (m) (d
d: 159.38 (C]O), 148.60 (C), 144.67 (C]N),
n
,
n
n
n
d
CHarom). Anal. Calcd for C15H25N5O: C, 61.83; H, 8.65; N, 24.03.
Found: C, 62.12; H, 8.69; N, 23.96.
MeCN). 1H NMR of the major isomer (300.13 MHz, DMSO-d6)
d:
7.17e7.23 (2H, m, ArH), 6.94 (1H, br s, NHNH2), 6.81e6.87 (2H, m,
ArH), 6.59 (1H, br d, 3J¼8.5 Hz, NHCH), 5.56 (2H, br s, NH2N]C),
4.84 (1H, ddd, 3J¼8.5, 3J¼8.0, 3J¼6.8 Hz, CHN), 4.07 (2H, br s,
NH2NH), 3.71 (3H, s, OCH3), 2.47 (1H, dd, 2J¼13.9, 3J¼6.8 Hz, HA in
CH2C]N), 2.45 (1H, dd, 2J¼13.9, 3J¼8.0 Hz, HB in CH2C]N), 1.58
(3H, s, CH3C]N); 1H NMR of the minor isomer (300.13 MHz, DMSO-
4.5.5. Hydrazone of 4-{[1-(4-methoxyphenyl)-2-methyl-3-oxo]but-
1-yl}semicarbazide (20e). Hydrazone 20e (0.746 g, 40%) as a mix-
ture of (E)- and (Z)-isomers in a ratio of 95:5 was prepared from
carbamate 18e (1.882 g, 6.74 mmol) in N2H4 (16 mL) (reflux, 23 h) as
described for 20a. An analytically pure sample (only E-isomer) was

9540
A.A. Fesenko, A.D. Shutalev / Tetrahedron 71 (2015) 9528e9543
obtained after crystallization from MeCN. Mp 179.5e180.5 ꢀC (dec,
MeCN). 1H NMR of the major isomer (300.13 MHz, DMSO-d6)
2J¼14.3, 3J¼7.7 Hz, HA in CH2C]N), 2.93 (1H, dd, 2J¼14.3, 3J¼7.4 Hz,
HB in CH2C]N), 2.25 (3H, s, CH3); 1H NMR of the minor isomer
d:
7.13e7.19 (2H, m, ArH), 6.89 (1H, br s, NHNH2), 6.81e6.87 (2H, m,
ArH), 6.74 (1H, br d, 3J¼8.8 Hz, NHCH), 5.57 (2H, br s, NH2N]C),
4.57 (1H, dd, 3J¼8.8, 3J¼8.7 Hz, CHN), 4.04 (2H, br s, NH2NH), 3.72
(3H, s, OCH3), 2.57 (1H, dq, 3J¼8.7, 3J¼7.0 Hz, CHC]N), 1.52 (3H, s,
CH3C]N), 0.82 (3H, d, 3J¼7.0 Hz, CH3CH); 1H NMR of the minor
(300.13 MHz, DMSO-d6) d: 7.42e7.47 (2H, m, ArH), 7.34e7.41 (1H,
m, ArH), 7.05e7.27 (6H, m, ArH, signals overlap with signals of ar-
omatic protons of the major isomer), 6.93 (1H, br s, NHNH2), 6.66
(1H, br d, 3J¼8.2 Hz, NHCH, signals partly overlap with the NH2N]C
proton signal of the major isomer), 6.62 (2H, br s, NH2N]C), 4.62
(1H, ddd, 3J¼8.7, 3J¼8.2, 3J¼6.5 Hz, CHN), z4.08 (2H, br s, NH2NH,
signal fully overlaps with signal of analogous protons of the major
isomer), 2.85 (1H, dd, 2J¼14.3, 3J¼6.5 Hz, HA in CH2C]N), 2.77 (1H,
dd, 2J¼14.3, 3J¼8.7 Hz, HB in CH2C]N), 2.25 (3H, s, CH3); 13C NMR of
isomer (300.13 MHz, DMSO-d6)
d
: 6.58 (1H, br d, 3J¼9.4 Hz, NHCH),
5.46 (2H, br s, NH2N]C), 4.75 (1H, dd, 3J¼9.4, 3J¼7.8 Hz, CHN), 2.67
(1H, dq, 3J¼7.8, 3J¼7.0 Hz, CHC]N), 1.48 (3H, s, CH3C]N), 0.94 (3H,
d, 3J¼7.0 Hz, CH3CH). Signals of other protons overlap with proton
signals of the major isomer; 13C NMR of the major isomer
the major isomer (75.48 MHz, DMSO-d6) d: 159.68 (C]O), 142.08
(75.48 MHz, DMSO-d6)
135.72 (C), 127.94 (2CH), 113.28 (2CH), 55.51 (CHN), 54.97 (OCH3),
47.27 (CHC]N), 16.25 (CH3C]N), 11.96 (CH3CH); IR (Nujol)
, cmꢁ1
3376 (s), 3306 (s), 3219 (br s) ( NH), 3107 (w), 3066 (br m), 3031
(w), 3012 (w) ( CHarom), 1664 (s), 1641 (s) (amide-I, C]N, NH2),
1615 (m), 1588 (w) ( CCarom), 1532 (s) (amide-II), 1515 (s) (
CCarom), 1249 (s), 1037 (m) ( CeO), 814 (s) ( CHarom). Anal. Calcd
d
: 159.41 (C]O), 157.79 (C), 149.16 (C]N),
(C]N), 140.53 (C), 138.98 (C), 135.90 (C), 128.73 (2CH), 127.90
(2CH), 126.68 (CH), 126.37 (2CH), 124.93 (2CH), 50.55 (CHN), 32.32
(CH2), 20.66 (CH3); 13C NMR of the minor isomer (75.48 MHz,
n
:
n
DMSO-d6)
134.24 (C), 128.91 (2CH), 128.59 (2CH), 128.22 (CH), 127.45 (2CH),
126.24 (2CH), 50.67 (CHN), 45.00 (CH2), 20.64 (CH3); IR (Nujol)
cmꢁ1: 3394 (m), 3346 (s), 3225 (br s) (
NH), 3056 (br m), 3018 (w)
NH2), 1578 (w), 1494 (w)
CCarom), 1534 (br s) (amide-II), 815 (m), 760 (m), 692 (m) (
d: 159.29 (C]O), 144.91 (C]N), 141.32 (C), 135.38 (C),
n
n
d
n
n
n,
n
d
n
for C13H21N5O2: C, 55.90; H, 7.58; N, 25.07. Found: C, 55.99; H, 7.62;
N, 25.35.
(
(
n
n
CHarom), 1658 (br s) (amide-I, n C]N, d
d
CHarom). Anal. Calcd for C17H21N5O: C, 65.57; H, 6.80; N, 22.49.
Found: C, 65.44; H, 7.07; N, 22.58.
4.5.6. Hydrazone
of
4-{[(3-oxo-1,3-diphenyl)prop-1-yl]}semi-
carbazide (20f). Hydrazone 20f (1.346 g, 46%) as a mixture of (E)-
and (Z)-isomers in a ratio of 75:25 was prepared from carbamate
18f (2.896 g, 9.74 mmol) in N2H4 (25 mL) (reflux, 19 h 40 min) as
described for 20a. An analytically pure sample (a 97:3 isomeric
ratio) was obtained after two crystallizations from MeCN. Mp
167e168.5 ꢀC (dec, MeCN). 1H NMR of the major isomer
4.5.8. Hydrazone of 4-{[1-(4-chlorophenyl)-3-oxo-3-phenyl]prop-1-
yl}semicarbazide (20h). Hydrazone 20h (0.870 g, 32%) as a mix-
ture of (E)- and (Z)-isomers in a ratio of 75:25 was prepared from
carbamate 18h (2.722 g, 8.20 mmol) in N2H4 (20 mL) (reflux, 20 h)
as described for 20a. An analytically pure sample (a 77:23 isomeric
ratio) was obtained after crystallization from MeCN. Mp
157.5e160 ꢀC (dec, MeCN). 1H NMR of the major isomer
(300.13 MHz, DMSO-d6) d: 7.46e7.52 (2H, m, ArH), 7.13e7.37 (8H,
m, ArH), 7.02 (1H, br s, NHNH2), 6.88 (1H, br d, 3J¼8.2 Hz, NHCH),
6.67 (2H, br s, NH2N]C), 4.93 (1H, ddd, 3J¼8.2, 3J¼7.8, 3J¼7.2 Hz,
CHN), 4.08 (2H, br s, NH2NH), 3.20 (1H, dd, 2J¼14.3, 3J¼7.8 Hz, HA in
CH2C]N), 2.95 (1H, dd, 2J¼14.3, 3J¼7.2 Hz, HB in CH2C]N); 1H NMR
(300.13 MHz, DMSO-d6) d: 7.15e7.55 (9H, m, ArH, signals overlap
with signals of aromatic protons of the minor isomer), 7.05 (1H, br
s, NHNH2), 6.95 (1H, br d, 3J¼8.2 Hz, NHCH), 6.67 (2H, br s, NH2N]
C), 4.94 (1H, ddd, 3J¼8.4, 3J¼8.2, 3J¼7.1 Hz, CHN), 4.09 (2H, br s,
NH2NH), 3.18 (1H, dd, 2J¼14.3, 3J¼8.4 Hz, HA in CH2C]N), 2.96 (1H,
dd, 2J¼14.3, 3J¼7.1 Hz, HB in CH2C]N); 1H NMR of the minor isomer
of the minor isomer (300.13 MHz, DMSO-d6) d: 7.42e7.47 (2H, m,
ArH), 7.13e7.40 (8H, m, ArH, signals overlap with signals of analo-
gous protons of the major isomer), 6.96 (1H, br s, NHNH2), 6.73 (1H,
br d, 3J¼8.4 Hz, NHCH), 5.67 (2H, br s, NH2N]C), 4.66 (1H, ddd,
3J¼8.7, 3J¼8.4, 3J¼6.2 Hz, CHN), 4.09 (2H, br s, NH2NH, signal
overlap with signal of analogous protons of the major isomer), 2.88
(1H, dd, 2J¼14.4, 3J¼6.2 Hz, HA in CH2C]N), 2.78 (1H, dd, 2J¼14.4,
3J¼8.7 Hz, HB in CH2C]N); 13C NMR of the major isomer
(300.13 MHz, DMSO-d6) d: 7.15e7.55 (9H, m, ArH, signals overlap
with signals of aromatic protons of the major isomer), 7.00 (1H, br s,
NHNH2), 6.79 (1H, br d, 3J¼8.2 Hz, NHCH), 5.69 (2H, br s, NH2N]C),
4.65 (1H, ddd, 3J¼8.4, 3J¼8.2, 3J¼6.5 Hz, CHN), 4.09 (2H, br s,
NH2NH, overlap with signal of analogous protons of the major
isomer), 2.88 (1H, dd, 2J¼14.4, 3J¼6.5 Hz, HA in CH2C]N), 2.80 (1H,
dd, 2J¼14.4, 3J¼8.4 Hz, HB in CH2C]N); 13C NMR of the major iso-
(75.48 MHz, DMSO-d6) d: 159.67 (C]O), 143.54 (C), 142.07 (C]N),
138.96 (C), 128.16 (2CH), 127.85 (2CH), 126.85 (CH), 126.65 (CH),
126.42 (2CH), 124.91 (2CH), 50.75 (CHN), 32.30 (CH2); 13C NMR of
mer (75.48 MHz, DMSO-d6) d: 159.56 (C]O), 142.80 (C), 141.92 (C]
the minor isomer (75.48 MHz, DMSO-d6)
(C]N), 144.43 (C), 134.23 (C), 128.94 (2CH), 128.32 (CH), 128.27
d
: 159.33 (C]O), 144.81
N), 138.87 (C), 131.23 (C), 128.38 (2CH), 127.97 (2CH), 127.96 (2CH),
126.77 (CH), 124.94 (2CH), 50.10 (CHN), 31.60 (CH2); 13C NMR of the
(CH), 128.07 (2CH), 127.47 (2CH), 126.33 (2CH), 51.02 (CHN), 44.99
minor isomer (75.48 MHz, DMSO-d6) d: 159.27 (C]O), 144.38 (C]
(CH2); IR (Nujol)
NH), 3105 (w), 3062 (w), 3026 (w) (
C]N, NH2), 1604 (w), 1586 (w) (
1496 (w) ( CCarom), 757 (s), 693 (s) (
16H19N5O: C, 64.63; H, 6.44; N, 23.55. Found: C, 64.59; H, 6.48; N,
23.76.
n
, cmꢁ1: 3393 (s), 3347 (s), 3319 (s), 3224 (br s) (
n
N), 143.41 (C), 134.11 (C), 130.87 (C), 128.93 (2CH), 128.32 (2CH),
128.27 (CH), 127.92 (2CH), 127.43 (2CH), 50.51 (CHN), 44.47 (CH2);
n
CHarom), 1658 (br vs) (amide-I,
CCarom), 1539 (s) (amide-II),
CHarom). Anal. Calcd for
n
d
n
IR (Nujol)
3060 (br m), 3021 (w) (
n
, cmꢁ1: 3387 (m), 3351 (s), 3320 (m), 3222 (br s) (
n
NH),
C]N,
n CCarom), 1542 (br vs) (amide-II), 1494
n
d
n
CHarom), 1658 (br vs) (amide-I,
n
C
d
NH2), 1600 (w), 1580 (w) (
(m) (
n
CCarom), 823 (m), 694 (m) (
d
CHarom). Anal. Calcd for
C16H18ClN5O: C, 57.92; H, 5.47; N, 21.11. Found: C, 57.89; H, 5.34; N,
4.5.7. Hydrazone of 4-{[1-(4-methylphenyl)-3-oxo-3-phenyl]prop-1-
yl}semicarbazide (20g). Hydrazone 20g (0.474 g, 28%) as a mixture
of (E)- and (Z)-isomers in a ratio of 84:16 was prepared from car-
bamate 18g (1.702 g, 5.46 mmol) in N2H4 (14 mL) (reflux, 24 h) as
described for 20a. An analytically pure sample (a 86:14 isomeric
ratio) was obtained after crystallization from MeCN. Mp
141e143.5 ꢀC (dec, MeCN). 1H NMR of the major isomer
21.15.
4.6. Acid-catalyzed cyclizations of 4-(
carbazide hydrazones
g-oxoalkyl)semi-
4 . 6 . 1. 7 , 14 - D i m e t h y l - 5 , 1 2 - d i p h e n y l - 1, 2 , 4 , 8 , 9 , 11 -
hexaazacyclotetradeca-7,14-diene-3,10-dione (24a). To semi-
(300.13 MHz, DMSO-d6)
d
: 7.47e7.53 (2H, m, ArH), 7.13e7.27 (5H,
carbazide 20a (0.171 g, 0.73 mmol) were added TsOH$H2O (0.143 g,
0.75 mmol) and EtOH (3.8 mL) and the obtained mixture was
refluxed for 1 h 50 min under stirring. The solvent was removed in
vacuo and the solid residue was triturated with saturated aqueous
m, ArH), 7.05e7.11 (2H, m, ArH), 7.02 (1H, br s, NHNH2), 6.83 (1H, br
d, 3J¼8.1 Hz, NHCH), 6.66 (2H, br s, NH2N]C), 4.88 (1H, ddd, 3J¼8.1,
3J¼7.7, 3J¼7.4 Hz, CHN), 4.08 (2H, br s, NH2NH), 3.16 (1H, dd,

A.A. Fesenko, A.D. Shutalev / Tetrahedron 71 (2015) 9528e9543
9541
NaHCO3 (1 mL). The obtained suspension was cooled (0 ꢀC) and the
precipitate was filtered, washed with ice-cold H2O and petroleum
ether, and dried to give 24a (0.126 g, 85%) as a mixture of trans- and
cis-diastereomers in a ratio of 96:4. An analytically pure sample
(only trans-isomer) was obtained after crystallization from DMF.
Mp 273 ꢀC (dec, DMF). 1H NMR of the trans-isomer (300.13 MHz,
DMSO-d6)
d
: 9.28 (2H, s, two NHN), 7.48 (2H, d, 3J¼7.4 Hz, two
NHC), 7.29e7.35 (4H, m, ArH), 6.88e6.94 (4H, m, ArH), 4.80e4.88
(2H, m, two CHN), 3.74 (6H, s, two OCH3), 2.52e2.64 (4H, m, two
CH2, signals partly overlap with signals of analogous protons of the
major isomer), 1.81 (6H, s, two CH3); 13C NMR of the trans-isomer
(75.48 MHz, DMSO-d6) d: 157.94 (2C), 155.27 (2C]O), 148.80 (2C]
DMSO-d6)
d
: 9.42 (2H, s, two NHN), 7.91 (2H, d, 3J¼7.6 Hz, two
N), 134.59 (2C), 126.76 (4CH), 113.57 (4CH), 55.02 (2 OCH3), 50.43
NHC), 7.20e7.37 (10H, m, ArH), 5.02 (2H, ddd, 3J¼7.6, 3J¼5.1,
3J¼4.2 Hz, two CHN), 2.69 (2H, dd, 2J¼14.0, 3J¼4.2 Hz, HA in two
CH2), 2.66 (2H, dd, 2J¼14.0, 3J¼5.1 Hz, HB in two CH2), 1.49 (6H, s,
(2CHN), 43.35 (2CH2), 19.18 (2CH3); 13C NMR of the cis-isomer
(75.48 MHz, DMSO-d6)
N), 136.00 (2C), 127.12 (4CH), 113.51 (4CH), 55.06 (2 OCH3), 50.75
(2CHN), 44.68 (2CH2), 16.83 (2CH3); IR (Nujol)
, cmꢁ1: 3371 (s),
3188 (br s), 3075 (br s) ( NH), 1666 (vs) (amide-I), 1612 (w), 1583
(w) ( CCarom), 1541 (s) ( C]N, amide-II), 1512 (s) ( CCarom), 1252
(s), 1036 (m) ( CeO), 828 (m) ( CHarom); MS (EI) m/z 468 [1,
d: 157.99 (2C), 155.89 (2C]O), 147.41 (2C]
two CH3); 1H NMR of the cis-isomer (300.13 MHz, DMSO-d6)
d
: 9.33
n
(2H, s, two NHN), 7.55 (2H, d, 3J¼7.3 Hz, two NHC), 7.20e7.44 (10H,
m, ArH, signals overlap with signals of analogous protons of the
major isomer), 4.90 (2H, ddd, 3J¼8.6, 3J¼7.3, 3J¼4.9 Hz, two CHN),
2.56e2.68 (4H, m, two CH2, signals partly overlap with signals of
analogous protons of the major isomer), 1.82 (6H, s, two CH3); 13C
n
n
n
n
n
d
(Mþ2)þ], 467 [6, (Mþ1)þ], 466 (22, Mþ), 352 (14), 309 (9), 267 (8),
234 (23), 233 (97), 218 (8), 217 (39), 190 (7), 189 (20), 174 (10), 163
(16), 162 (96), 137 (10), 136 (98), 135 (17), 134 (46), 121 (11), 109 (9),
91 (13), 77 (9), 18 (100). Anal. Calcd for C24H30N6O4: C, 61.79; H,
6.48; N, 18.01. Found: C, 61.57; H, 6.48; N, 18.19.
NMR of the trans-isomer (75.48 MHz, DMSO-d6) d: 155.33 (2C]O),
148.78 (2C]N), 142.74 (2C), 128.22 (4CH), 126.65 (2CH), 125.71
(4CH), 51.12 (2CHN), 43.33 (2CH2), 19.11 (2CH3); IR of the trans-
isomer (Nujol)
1674 (vs), 1638 (w) (amide-I),1584 (w) (
amide-II),1495 (m) ( CCarom), 756 (s), 696 (s) (
n
, cmꢁ1: 3371 (s), 3197 (s), 3087 (s), 3032 (m) (
n
NH),
C]N,
d CHarom); MS (EI) m/
n
CCarom), 1550 (vs) (
n
4.6.4. 7,14-Dimethyl-5,12-di(4-tert-butylphenyl)-1,2,4,8,9,11-
hexaazacyclotetradeca-7,14-diene-3,10-dione (24d). Compound 24d
(0.331 g, 93%) as a mixture of trans- and cis-diastereomers in a ratio
of 55:45 was prepared from semicarbazide 20d (0.401 g,
1.37 mmol) and TsOH$H2O (0.279 g, 1.47 mmol) in EtOH (18 mL)
(reflux, 1 h 50 min) as described for 24a. An analytically pure
sample (only trans-isomer) was obtained after crystallization from
DMF. Mp 308.5 ꢀC (dec, DMF). 1H NMR of the trans-isomer
n
z 407 [5, (Mþ1)þ], 406 (21, Mþ), 335 (1), 301 (1), 292 (7), 244 (8),
204 (13), 203 (29), 187 (10), 159 (6), 144 (3), 132 (24), 106 (100), 104
(17), 91 (8), 77 (16), 44 (12). Anal. Calcd for C22H26N6O2: C, 65.01; H,
6.45; N, 20.68. Found: C, 64.99; H, 6.53; N, 20.77.
4.6.2. 7,14-Dimethyl-5,12-di(4-methylphenyl)-1,2,4,8,9,11-
hexaazacyclotetradeca-7,14-diene-3,10-dione (24b). Compound 24b
(0.252 g, 92%) as a mixture of trans- and cis-diastereomers in a ratio
of 71:29 was prepared from semicarbazide 20b (0.314 g,1.26 mmol)
and TsOH$H2O (0.254 g, 1.33 mmol) in EtOH (6.2 mL) (reflux, 1 h
50 min) as described for 24a. An analytically pure sample was ob-
tained after crystallization from AcOH.30 Mp 315 ꢀC (dec, AcOH). 1H
(300.13 MHz, DMSO-d6) d: 9.36 (2H, s, two NHN), 7.91 (2H, d,
3J¼7.5 Hz, two NHC), 7.32e7.38 (4H, m, ArH), 7.15e7.21 (4H, m,
ArH), 4.96 (2H, ddd, 3J¼7.5, 3J¼5.2, 3J¼4.1 Hz, two CHN), 2.68 (2H,
dd, 2J¼14.2, 3J¼4.1 Hz, HA in two CH2), 2.64 (2H, dd, 2J¼14.2,
3J¼5.2 Hz, HB in two CH2), 1.52 (6H, s, two CH3C]N), 1.27 (18H, s,
CH3 in two t-Bu); 1H NMR of the cis-isomer (300.13 MHz, DMSO-d6)
NMR of the trans-isomer (300.13 MHz, DMSO-d6)
d
: 9.36 (2H, s, two
d
: 9.30 (2H, s, two NHN), 7.54 (2H, d, 3J¼7.3 Hz, two NHC), 7.30e7.39
NHN), 7.87 (2H, d, 3J¼7.8 Hz, two NHC), 7.11e7.17 (8H, m, two ArH),
4.99 (2H, ddd, 3J¼7.8, 3J¼4.9, 3J¼4.2 Hz, two CHN), 2.66 (2H, dd,
2J¼14.1, 3J¼4.9 Hz, HA in two CH2), 2.64 (2H, dd, 2J¼14.1, 3J¼4.9 Hz,
HB in two CH2), 2.28 (6H, s, CH3 in two CH3C6H4), 1.49 (6H, s, two
(8H, m, ArH, signals partly overlap with signals of aromatic protons
of the major isomer), 4.84 (2H, ddd, 3J¼9.0, 3J¼7.3, 3J¼5.2 Hz, two
CHN), 1.82 (6H, s, two CH3C]N), 1.28 (18H, s, CH3 in two t-Bu).
Proton signals of two CH2 group overlap with signals of analogous
protons of the major isomer; 13C NMR of the trans-isomer
CH3C]N); 1H NMR of the cis-isomer (300.13 MHz, DMSO-d6)
d:
9.29 (2H, s, two NHN), 7.53 (2H, d, 3J¼7.5 Hz, two NHC), 7.26e7.32
(4H, m, ArH), 7.13e7.19 (4H, m, ArH), 4.85 (2H, ddd, 3J¼8.3, 3J¼7.5,
3J¼4.7 Hz, two CHN), 2.53e2.70 (4H, m, two CH2, signals partly
overlap with signals of analogous protons of the major isomer),
2.29 (6H, s, CH3 in two CH3C6H4), 1.80 (6H, s, two CH3C]N); IR
(75.48 MHz, DMSO-d6) d: 155.31 (2C]O), 148.98 (2C]N), 148.88
(2C), 139.82 (2C), 125.40 (4CH), 124.90 (4CH), 50.88 (2CHN), 43.02
(2CH2), 34.13 (2CMe3), 31.18 (6ꢂCH3 in 2 t-Bu), 19.11 (2CH3C]N);
13C NMR of the cis-isomer (75.48 MHz, DMSO-d6)
d: 155.85 (2C]O),
148.88 (2C]N), 147.63 (2C), 140.98 (2C), 125.76 (4CH), 124.82
(4CH), 51.08 (2CHN), 44.34 (2CH2), 34.13 (2CMe3), 31.18 (6ꢂCH3 in
(Nujol) n n NH), 1674
, cmꢁ1: 3366 (s), 3190 (s), 3084 (s), 3027 (w) (
(vs), 1636 (m) (amide-I), 1544 (vs) (
n
C]N, amide-II), 1518 (sh) (
n
2 t-Bu), 16.97 (2CH3C]N); IR of the trans-isomer (Nujol) n :
, cmꢁ1
CCarom), 808 (s) (
d
CHarom); MS (EI) m/z 435 [4, (Mþ1)þ], 434 (15,
3371 (s), 3197 (br s), 3090 (br s) (
(vs) (amide-I),1638 (w),1613 (w) (
N, amide-II), 1517 (w) ( CCarom), 827 (m) (
n
n
NH), 3022 (w) (
CCarom),1554 (s),1543 (s) (
CHarom); MS (EI) m/z
n
CHarom), 1672
Mþ), 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 C24H30N6O2: C, 66.34; H, 6.96; N, 19.34. Found: C, 66.10; H,
6.88; N, 19.46.
n
C]
n
d
520 [3, (Mþ2)þ], 519 [16, (Mþ1)þ], 518 (47, Mþ), 447 (7), 404 (30),
361 (13), 300 (41), 260 (98), 259 (97), 244 (28), 243 (87), 217 (23),
216 (22), 215 (48), 200 (21),199 (23),189 (40),188 (99),186 (26),173
(86), 163 (96), 162 (99), 160 (32), 159 (27), 158 (33), 147 (68), 146
(82), 145 (56), 144 (42), 132 (45), 118 (29), 117 (34), 115 (21), 91 (36),
18 (100). Anal. Calcd for C30H42N6O2: C, 69.47; H, 8.16; N, 16.20.
Found: C, 69.32; H, 8.17; N, 16.22.
4.6.3. 7,14-Dimethyl-5,12-di(4-methoxyphenyl)-1,2,4,8,9,11-
hexaazacyclotetradeca-7,14-diene-3,10-dione (20c). Compound 24c
(0.282 g, 86%) as a mixture of trans- and cis-diastereomers in a ratio
of 69:31 was prepared from semicarbazide 20c (0.373 g, 1.40 mmol)
and TsOH$H2O (0.284 g, 1.49 mmol) in EtOH (7 mL) (reflux, 1 h
50 min) as described for 24a. An analytically pure sample (trans/
cis¼97:3) was obtained after crystallization from DMF. Mp 289 ꢀC
4.6.5. 6,7,13,14-Tetramethyl-5,12-di(4-methoxyphenyl)-1,2,4,8,9,11-
hexaazacyclotetradeca-7,14-diene-3,10-dione
(24e). To
semi-
(dec, DMF). 1H NMR of the trans-isomer (300.13 MHz, DMSO-d6)
d
:
carbazide 20e (0.528 g, 1.89 mmol) were added TsOH$H2O (0.372 g,
1.96 mmol) and EtOH (7 mL) and the obtained mixture was refluxed
for 1 h 50 min under stirring. The obtained suspension was cooled
(0 ꢀC). The precipitate was filtered, washed with cold (ꢁ18 ꢀC) EtOH
(2ꢂ3 mL), ice-cold H2O (4ꢂ3 mL) and petroleum ether, and dried to
give 24e (0.340 g, 73%) as a mixture of seven diastereomers, three of
9.33 (2H, s, two NHN), 7.88 (2H, d, 3J¼7.9 Hz, two NHC), 7.15e7.21
(4H, m, ArH), 6.86e6.93 (4H, m, ArH), 4.99 (2H, ddd, 3J¼7.9, 3J¼4.8,
3J¼4.3 Hz, two CHN), 3.73 (6H, s, two OCH3), 2.66 (2H, dd, 2J¼14.1,
3J¼4.3 Hz, HA in two CH2), 2.64 (2H, dd, 2J¼14.1, 3J¼4.8 Hz, HB in two
CH2), 1.51 (6H, s, two CH3); 1H NMR of the cis-isomer (300.13 MHz,

9542
A.A. Fesenko, A.D. Shutalev / Tetrahedron 71 (2015) 9528e9543
which (a 81:13:6 isomeric ratio) give 97 mol % in total. An analyt-
ically pure sample (a 87:12:1 isomeric ratio, respectively) was ob-
tained after crystallization from n-BuOH. Mp 256.5 ꢀC (dec, n-
BuOH). 1H NMR of the major isomer (81%) (300.13 MHz, DMSO-d6)
silica gel 60 (11 g) eluting with CHCl3epetroleum ether (from 5:1 to
1:0) to afford pure 29b (0.201 g, 45%). Mp 189e191 ꢀC (EtOH). 1H
NMR (300.13 MHz, DMSO-d6)
d
: 9.59 (1H, br d, 4J¼2.1 Hz, N(2)H),
7.39e7.46 (2H, m, ArH), 7.31 (1H, br dd of unresolved d, 3J¼4.0,
4J¼2.1, 4Jz0.8 Hz, N(4)H, signals partly overlap with signals of ar-
omatic protons), 7.22e7.31 (3H, m, ArH), 7.16e7.21 (2H, m, ArH),
7.06e7.11 (2H, m, ArH), 4.74 (1H, ddd, 3J¼7.0, 3J¼4.0, 3J¼3.1 Hz, H-
5), 3.33 (1H, ddd, 2J¼14.5, 3J¼7.0, 4J¼0.8 Hz, HA-6), 3.13 (1H, dd,
2J¼14.5, 3J¼3.1 Hz, HB-6), 2.22 (3H, s, CH3); 13C NMR (75.48 MHz,
d
: 8.93 (2H, s, two NHN), 7.30e7.37 (4H, m, ArH), 6.91e6.96 (4H, m,
ArH), 6.56 (2H, d, 3J¼10.6 Hz, two NHC), 4.93 (2H, dd, 3J¼11.5,
3J¼10.6 Hz, two CHN), 3.74 (6H, s, two OCH3), 2.82 (2H, dq, 3J¼11.5,
3J¼7.0 Hz, two CHCH3), 1.79 (6H, s, two CH3C]N), 0.66 (6H, d,
3J¼7.0 Hz, two CH3CH); 1H NMR of the first minor isomer (13%)
(300.13 MHz, DMSO-d6)
d: 9.30 (2H, s, two NHN), 8.27 (2H, br d,
DMSO-d6)
(C), 128.77 (3CH), 128.15 (2CH), 125.87 (2CH), 125.65 (2CH), 55.46
(C-5), 36.24 (C-6), 20.61 (CH3); IR (Nujol)
, cmꢁ1: 3330 (w), 3249
(br s), 3191 (br m), 3092 (br s) ( NH), 3016 (w) ( CHarom), 1683 (s)
(amide-I and C]N), 1616 (w), 1595 (w), 1575 (w), 1497 (w) (
CCarom), 803 (s), 760 (m), 697 (m) ( CHarom); MS (EI) m/z 281 [1,
d: 155.60 (C-3),154.99 (C-7),140.25 (C),137.73 (C),136.22
3J¼8.6 Hz, two NHC), 7.20e7.26 (4H, m, ArH), 6.89e6.95 (4H, m,
ArH), 4.76 (2H, dd, 3J¼8.6, 3J¼4.0 Hz, two CHN), 3.75 (6H, s, two
OCH3), 2.86 (2H, dq, 3J¼7.0, 3J¼4.0 Hz, two CHCH3, signals partly
overlap with signals of analogous protons of the major isomer), 1.57
(6H, s, two CH3C]N),1.24 (6H, d, 3J¼7.0 Hz, two CH3CH); 1H NMR of
n
n
n
n
n
d
the second minor isomer (6%) (300.13 MHz, DMSO-d6)
d
: 9.43 (2H,
(Mþ2)þ], 280 [8, (Mþ1)þ], 279 (42, Mþ), 235 (34), 221 (5), 191 (6),
189 (4), 178 (3), 174 (3), 165 (4), 162 (8), 161 (59), 147 (5), 146 (51),
145 (13), 133 (12), 132 (3), 128 (4), 127 (3), 120 (5), 119 (19), 118 (99),
117 (22),116 (5), 115 (10),105 (4),104 (8), 103 (20),102 (4), 92 (5), 91
(29), 90 (3), 89 (5), 78 (3), 77 (14), 18 (100). Anal. Calcd for
s, two NHN), 7.94 (2H, br d, 3J¼10.3 Hz, two NHC), 1.41 (6H, s, two
CH3C]N). Signals of other protons overlap with proton signals of
other isomers; 13C NMR of the major isomer (81%) (75.48 MHz,
DMSO-d6) d: 158.33 (2C), 155.02 (2C]O), 152.39 (2C]N), 134.02
(2C), 128.51 (4CH), 113.95 (4CH), 55.04 (2 OCH3), 54.20 (2CHN),
C17H17N3O$0.11EtOH: C, 72.72; H, 6.26; N, 14.78. Found: C, 72.46; H,
6.22; N, 14.81.
47.46 (2CHCH3), 16.36 (2CH3C]N), 11.47 (2CH3CH); 13C NMR of the
first minor isomer (13%) (75.48 MHz, DMSO-d6) d: 157.88 (2C),
155.83 (2C]O), 152.89 (2C]N), 135.24 (2C), 127.02 (4CH), 113.46
(4CH), 56.10 (2CHN), 55.00 (2 OCH3), 46.15 (2CHCH3). Signals of the
4.6.8. 5-(4-Chlorophenyl)-7-phenyl-2,4,5,6-tetrahydro-3H-1,2,4-
triazepin-3-one (29c). Triazepine 29c was prepared from semi-
carbazide 20h (0.346 g, 1.04 mmol) and TsOH$H2O (0.203 g,
1.06 mmol) in EtOH (45 mL) (reflux, 1 h 50 min) as described for
24a. The crude product was purified by column chromatography on
silica gel 60 (10 g) eluting with CHCl3 to afford pure 29c (0.129 g,
41%). Mp 200.5e201.5 ꢀC (EtOH). 1H NMR (300.13 MHz, DMSO-d6)
other methyl groups are not detectable; IR (Nujol)
m), 3371 (m), 3213 (br s), 3087 (br m) ( NH), 1675 (vs) (amide-I),
1612 (w), 1584 (w) ( CCarom), 1529 (s), 1512 (s) ( C]N, amide-II),
1253 (s), 1034 (m) ( CeO), 835 (m) ( CHarom); MS (EI) m/z 496 [2,
n
, cmꢁ1: 3401 (br
n
n
n
n
d
(Mþ2)þ], 495 [9, (Mþ1)þ], 494 (20, Mþ), 254 (17), 248 (59), 247
(96), 232 (11), 231 (27), 204 (19), 203 (25), 189 (12), 188 (12), 163
(19),162 (96),148 (19),147 (11),137 (11),136 (98),135 (83),134 (97),
121 (11), 119 (13), 91 (15), 77 (14), 18 (100). Anal. Calcd for
d
: 9.65 (1H, br d, 4J¼2.1 Hz, N(2)H), 7.39e7.45 (2H, m, ArH), 7.38 (1H,
br dd of unresolved d, 3J¼4.2, 4J¼2.1, 4Jz0.9 Hz, N(4)H), 7.22e7.36
(7H, m, ArH), 4.82 (1H, ddd, 3J¼6.7, 3J¼4.2, 3J¼3.2 Hz, H-5), 3.36 (1H,
ddd, 2J¼14.4, 3J¼6.7, 4J¼0.9 Hz, HA-6), 3.18 (1H, dd, 2J¼14.4,
C
26H34N6O4$0.25H2O: C, 62.57; H, 6.97; N,16.84. Found: C, 62.32; H,
7.01; N, 16.56.
3J¼3.2 Hz, HB-6); 13C NMR (75.48 MHz, DMSO-d6)
d: 155.43 (C-3),
155.17 (C-7), 142.13 (C), 137.51 (C), 131.63 (C), 128.88 (CH), 128.15
(4CH), 127.92 (2CH), 125.60 (2CH), 55.22 (C-5), 35.74 (C-6); IR
4.6.6. 5,7-Diphenyl-2,4,5,6-tetrahydro-3H-1,2,4-triazepin-3-one
(29a). Triazepine 29a was prepared from semicarbazide 20f
(1.344 g, 4.52 mmol) and TsOH$H2O (0.893 g, 4.70 mmol) in EtOH
(150 mL) (1 h 50 min, reflux) as described for 24a. The crude
product was purified by column chromatography on silica gel 60
(31 g) eluting with CHCl3eMeOH (from 100:0 to 200:1), the main
fraction was concentrated and crystallized from EtOH (15 mL) to
give 29a (0.472 g, 39%). Mp 204e205 ꢀC (EtOH). 1H NMR
(Nujol)
1683 (s) (amide-I), 1632 (m) (
1488 (w) ( CCarom), 819 (s), 762 (m), 701 (m) (
n
, cmꢁ1: 3239 (br s), 3095 (br s) (
n
NH), 3023 (w) (
C]N), 1600 (w), 1577 (w), 1510 (w),
CHarom); MS (EI) m/
n CHarom),
n
n
d
z 302 [3, (Mþ3)þ], 301 [16, (Mþ2)þ], 300 [9, (Mþ1)þ], 299 (46, Mþ),
257 (9), 256 (6), 255 (27), 214 (4), 199 (4), 192 (4), 191 (7), 189 (8),
188 (5), 168 (5), 166 (15),165 (5), 162 (20), 161 (98), 146 (6), 145 (14),
140 (10), 139 (5), 138 (23), 133 (22), 127 (6), 125 (4), 119 (6), 118 (18),
117 (5), 115 (7), 111 (7), 110 (4), 104 (9), 103 (30), 102 (7), 92 (4), 91
(17), 89 (6), 77 (23), 76 (4), 75 (5), 18 (100). Anal. Calcd for
(300.13 MHz, DMSO-d6)
d
: 9.62 (1H, br d, 4J¼2.1 Hz, N(2)H),
7.36e7.43 (2H, m, ArH), 7.35 (1H, br dd of unresolved d, 3J¼4.2,
4J¼2.1, 4Jz0.7 Hz, N(4)H), 7.14e7.33 (8H, m, ArH), 4.81 (1H, ddd,
3J¼6.7, 3J¼4.2, 3J¼3.2 Hz, H-5), 3.34 (1H, ddd, 2J¼14.4, 3J¼6.7,
4J¼0.7 Hz, HA-6), 3.18 (1H, dd, 2J¼14.4, 3J¼3.2 Hz, HB-6); 13C NMR
C16H14ClN3O: C, 64.11; H, 4.71; N, 14.02. Found: C, 64.04; H, 4.69; N,
13.92.
(75.48 MHz, DMSO-d6) d: 155.58 (C-3), 155.37 (C-7), 143.19 (C),
Acknowledgements
137.63 (C), 128.80 (CH), 128.25 (2CH), 128.12 (2CH), 127.20 (CH),
125.97 (2CH), 125.64 (2CH), 55.90 (C-5), 36.10 (C-6); IR (Nujol)
cmꢁ1: 3347 (w), 3243 (br s), 3226 (br s), 3098 (br s), 3060 (m),
3032 (m) ( NH), 1685 (s) (amide-I), 1639 (br m) ( C]N), 1588
(w), 1511 (w) ( CCarom), 767 (m), 698 (s) ( CHarom); MS (EI) m/z
n
,
This research was financially supported by the Russian Foun-
dation for Basic Research (Grant No. 15-03-07564) and the Ministry
of Education and Science of the Russian Federation (project part of
government order, 4.1849.2014/K).
n
n
n
d
266 [2, (Mþ1)þ], 265 (14, Mþ), 221 (13), 162 (11), 161 (100), 145
(14), 133 (17), 132 (16), 119 (7), 118 (15), 115 (8), 104 (31), 103 (31),
102 (5), 92 (5), 91 (23), 89 (6), 78 (11), 77 (46). Anal. Calcd for
Supplementary data
C
16H15N3O: C, 72.43; H, 5.70; N, 15.84. Found: C, 72.39; H, 5.65; N,
15.67.
Supplementary data (copies of IR spectra of all the synthesized
compounds, copies of 1H and 13C NMR spectra of compounds
24aee, 29aec, copies of 1H,1H-NOESY spectra of compounds 20a,h)
associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2015.10.079. These data include MOL
files and InChiKeys of the most important compounds described in
this article.
4.6.7. 5-(4-Methylphenyl)-7-phenyl-2,4,5,6-tetrahydro-3H-1,2,4-
triazepine-3-one (29b). Triazepine 29b was prepared from semi-
carbazide 20g (0.471 g, 1.51 mmol) and TsOH$H2O (0.280 g,
1.58 mmol) in EtOH (50 mL) (reflux, 1 h 50 min) as described for
24a. The crude product was purified by column chromatography on

A.A. Fesenko, A.D. Shutalev / Tetrahedron 71 (2015) 9528e9543
9543
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18. At the beginning of the current study, we attempted to prepare compounds 7
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