Cleavage of Pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones with Thiocarbonohydrazide. Synthesis of Substituted 4-Amino-1,2,4-triazines

Article abstract of DOI:10.1134/S1070428019070182

3-Acylpyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones reacted with thiocarbonohydrazide to give mixtures of 4-amino-6-(acylmethyl)-3-sulfanylidene-3,4-dihydro-1,2,4-triazin-5(2H)-ones and 6-substituted 1,4-benzoxazine-2,3-diones which can be separated by fractional crystallization directly from the reaction mixture. The reaction is likely to involve a sequence of nucleophilic transformations with intermediate formation of spiro[pyrrole-2,6′-[1,2,4]triazines] which undergo cleavage of the C²-N¹ bond in the pyrrole ring. The structure of the products was determined by X-ray analysis, and intermediate products were identified by UPLC/MS. 1,2,4-Triazine derivatives can also be synthesized independently from alkyl 2,4-dioxobutanoates or 2-oxobutanedioic acid and thiocarbonohydrazide. The known procedure for the synthesis of 4-amino-1,2,4-triazines from 4-aryl-2,4-dioxobutanoic acids and thiocarbonohydrazide was improved to meet the “green chemistry” principles. Two new methods for the synthesis of substituted 4-amino-1,2,4-triazines were developed. The obtained compounds attract interest for medicinal chemistry, pharmacology, and fine organic synthesis.

Full text of DOI:10.1134/S1070428019070182

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 7, pp. 1013–1018. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Organicheskoi Khimii, 2019, Vol. 55, No. 7, pp. 1120–1126.
Cleavage of Pyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones
with Thiocarbonohydrazide. Synthesis of Substituted
4
-Amino-1,2,4-triazines
a
a
a
a
A. I. Kobelev , E. E. Stepanova , M. V. Dmitriev , and A. N. Maslivets *
Perm State University, Perm, Russia
*
e-mail: koh2@psu.ru
Received March 11, 2019; revised April 5, 2019; accepted April 23, 2019
Abstract—3-Acylpyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones reacted with thiocarbonohydrazide to give
mixtures of 4-amino-6-(acylmethyl)-3-sulfanylidene-3,4-dihydro-1,2,4-triazin-5(2H)-ones and 6-substituted
1
,4-benzoxazine-2,3-diones which can be separated by fractional crystallization directly from the reaction
mixture. The reaction is likely to involve a sequence of nucleophilic transformations with intermediate
2
1
formation of spiro[pyrrole-2,6′-[1,2,4]triazines] which undergo cleavage of the C –N bond in the pyrrole ring.
The structure of the products was determined by X-ray analysis, and intermediate products were identified by
UPLC/MS. 1,2,4-Triazine derivatives can also be synthesized independently from alkyl 2,4-dioxobutanoates or
2
-oxobutanedioic acid and thiocarbonohydrazide. The known procedure for the synthesis of 4-amino-1,2,4-
triazines from 4-aryl-2,4-dioxobutanoic acids and thiocarbonohydrazide was improved to meet the “green
chemistry” principles. Two new methods for the synthesis of substituted 4-amino-1,2,4-triazines were
developed. The obtained compounds attract interest for medicinal chemistry, pharmacology, and fine organic
synthesis.
Keywords: 1H-pyrrole-2,3-diones, hetareno[e]pyrrole-2,3-diones, pyrrolobenzoxazinetriones, thiocarbonohy-
drazide, 1,2,4-triazines, 1,4-benzoxazine, X-ray analysis, 2,4-dioxobutanoic acid esters, divergent synthesis,
green chemistry.
DOI: 10.1134/S1070428019070182
Divergent synthesis becomes a more and more
popular approach to the creation of small molecule
libraries for the search for drug candidates. This
approach makes it possible to obtain series of struc-
turally diverse compounds from the same set of initial
reagents, thus providing more efficient exploration of
chemical space. Implementation of this approach
requires search for accessible polyfunctional com-
pounds and study of their chemical properties.
[2,1-c][1,4]benzoxazine-1,2,4-triones which may be
regarded as derivatives of 1H-pyrrole-2,3-diones with
a fused 1,4-benzoxazinone fragment.
The reactions of 3-acylpyrrolo[2,1-c][1,4]benzoxa-
zine-1,2,4-triones 1a–1h with thiocarbonohydrazide
were carried out by heating a solution of equimolar
amounts of the reactants in boiling anhydrous 1,4-di-
oxane for 1–3 min (until violet color typical of initial
compounds 1a–1h disappeared). The products, 6-acyl-
2H-1,4-benzoxazine-2,3(4H)-diones 2a and 2b and
4-amino-6-(acylmethyl)-3-sulfanylidene-3,4-dihydro-
1,2,4-triazin-5(2H)-ones 3a–3g [14] (Scheme 1) were
isolated by fractional crystallization directly from the
reaction mixtures. The structures of 2a and 3a were
confirmed by X-ray analysis (Figs. 1, 2). According to
the X-ray diffraction data, compounds 2a and 3a crys-
tallized in centrosymmetric space groups belonging to
the monoclinic crystal system. A single crystal of 3a
was a 1:1 solvate with 1,4-dioxane. The bond lengths,
1
H-Pyrrole-2,3-diones are readily accessible poly-
electrophiles which were used as initial structures to
develop divergent synthetic approaches to various
heterocyclic system [1–7]. Thiocarbonohydrazide is
a commercially available polynucleophile possessing
five nucleophilic centers which endow it with a broad
synthetic potential. It was used to obtain functionalized
heterocyclic compounds [8, 9] which exhibited bio-
logical activity [10–13]. In this work we studied the
reaction of thiocarbonohydrazide with 3-acylpyrrolo-
1
013

1
014
KOBELEV et al.
Scheme 1.
O
O
N
O
O
S
O
O
O
R
NH2
O
N
+
H
2
N
NH
2
+
R'
N
N
O
N
R
H
H
R'
N
H
N
H
S
O
1
a–1h
2a, 2b
3a–3g
1
, R = Ph, R′ = H (a), Cl (b), R = C
6
H
4
OEt-4, R′ = H (c), R = C
6
H
4
Cl-4 (d), R = C
6
H
4
Br-4, R′ = H (e), R = C
6
H
4
OMe-4, R′ = H (f),
Br-4 (d),
R = C
6
H
4
Me-4, R′ = H (g), R = OEt, R′ = H (h); 2, R′ = H (a), Cl (b); 3, R = Ph (a), C
OMe-4 (e), C Me-4 (f), OEt (g).
6
H
4
OEt-4 (b), C Cl-4 (c), C H
6
H
4
6 4
C
6
H
4
6 4
H
bond angles, and geometric parameters of cyclic frag-
ments of both compounds did not differ from the cor-
responding values for structurally related heterocycles.
as an aminal [15]; cleavage of the C–N bond in the
pyrrole ring of intermediate A is followed by intra-
molecular attack of the phenolic hydroxy group on the
ketone carbonyl group and cleavage of the adjacent
C–C bond, thus yielding compounds 2 and 3.
The described reaction is likely to involve a se-
quence of nucleophilic transformations (Scheme 2).
The first stage is addition of the primary amino group
In order to confirm the proposed scheme, the
reaction mixtures obtained by keeping compound 1a
and thiocarbonohydrazide in 1,4-dioxane at room tem-
perature for 1, 5, 20, 50, 110, and 170 min and 24 h
were analyzed by ULPC/MS. The chromatograms re-
corded in 5, 20, 50, 110, and 170 min after the reaction
started contained peaks corresponding to initial com-
pounds, products 2a and 3a, and additional peaks
which were assigned to intermediate products. The
mass spectra corresponding to the latter displayed ion
3
a
of thiocarbonohydrazide to C of 1. Next follows
intramolecular nucleophilic attack of the NH group of
the carbothiohydrazide fragment on the lactone car-
bonyl carbon atom of the benzoxazine ring, which is
4
5
accompanied by cleavage of the C ‒O , to give inter-
mediate spiro compound A. The latter can be regarded
2
3
O
8
O
C
+
–
7
3
C
C
peaks with m/z 426 [M + H] (ESI+) and 424 [M – H]
2
(ESI–); i.e., the molecular weight (M) matches the sum
C
C H NO + CH N S which is expected for interme-
diate products in support of the proposed scheme.
1
8
9
5
6
4
1
C
1
O
According to published data [16], compounds 3a,
3d, and 3g can be synthesized by reaction of thio-
carbonohydrazide with 4-aryl-2,4-dioxobutanoic acids
in boiling 1,4-dioxane (1 h). We improved the reported
procedure to meet the “green chemistry” requirements
4
6
C
C
1
N
5
C
Fig. 1. Structure of the molecule of 2H-1,4-benzoxazine-
,3(4H)-dione (2a) according to the X-ray diffraction data.
[
17], namely harmful 1,4-dioxane was replaced by
2
Non-hydrogen atoms are shown as thermal vibration ellip-
soids with a probability of 50%.
a “green solvent,” ethanol [18], and more soluble and
accessible methyl 4-aryl-2,4-dioxobutanoates were
used instead of the corresponding acids. Methyl 4-aryl-
2,4-dioxobutanoates 4a–4f and diethyl 2-oxobutane-
dioate (4g) reacted with an equimolar amount of
thiocarbonohydrazide on heating in boiling ethanol for
1.5–2 h to afford 1,2,4-triazines 3a–3g in good yields
1
N
N
1
O
2
7
2
O
C
8
1
2
C
S
C
1
6
C
C
3
C
5
C
9
C
(
Scheme 3).
4
C
10
C
4
11
In summary, we have shown that the reaction of
3
N
C
N
3
-acylpyrrolo[2,1-c][1,4]benzoxazine-1,2,4-triones
Fig. 2. Structure of the molecule of 4-amino-6-(2-oxo-2-
phenylethyl)-3-sulfanylidene-3,4-dihydro-1,2,4-triazin-
with thiocarbonohydrazide leads to the formation of
mixtures of 6-substituted 2H-1,4-benzoxazine-
5
(2H)-one (3a) according to the X-ray diffraction data. Non-
2
,3(4H)-diones and 6-(acylmethyl)-4-amino-3-sul-
hydrogen atoms are shown as thermal vibration ellipsoids
with a probability of 50%.
fanylidene-3,4-dihydro-1,2,4-triazin-5(2H)-ones,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 7 2019

CLEAVAGE OF PYRROLO[2,1-c][1,4]BENZOXAZINE-1,2,4-TRIONES
1015
Scheme 2.
HN NH2
S
O
N
O
O
O
N
O
HN
S
O
NH
+
H
2
N
NH
2
R'
R'
C(O)R
N
N
R
H
H
O
O
OH
1
R'
H
O
2
N
S
R'
S
H N
2
N
N
NH
NH
O
NH
NH
C(O)R
2 + 3
N
N
OH
OH
O
C(O)R
O
OH
O
A
which attract interest for medicinal chemistry, pharma-
cology, and fine organic synthesis. The known proce-
dure for the synthesis of 4-amino-1,2,4-triazines has
been improved to meet the “green chemistry” prin-
ciples. 4-Amino-1,2,4-triazines have been synthesized
by two methods: by reactions of thiocarbonohydrazide
with pyrrolobenzoxazinetriones and 4-aryl-2,4-dioxo-
butanoates, so that pyrrolobenzoxazinetriones can be
regarded as synthetic equivalents of acylpyruvic acids.
tor (λ 230–780 nm), and Xevo TQD mass-selective
detector (electrospray ionization, positive and negative
ion detection; ion source temperature 150°C, capillary
voltage 3500–4000 V, cone voltage 20–70 V, vaporiza-
tion temperature 150–300°C). The purity of the
isolated compounds was checked by TLC on Silica gel
60 F254 plates (Merck) using toluene, ethyl acetate, or
toluene–ethyl acetate (5 :1) as eluent; spots were
visualized by treatment with iodine vapor or under UV
light (λ 254 nm).
EXPERIMENTAL
2H-1,4-Benzoxazine-2,3(4H)-dione (2a). Thiocar-
bonohydrazide, 0.106 g (1.0 mmol), was added to a so-
lution of 0.319 g (1.0 mmol) of compound 1a in 15 mL
of anhydrous 1,4-dioxane, and the mixture was
refluxed for 1–3 min until the violet color typical of 1a
disappeared. The mixture was cooled and partly evapo-
rated until a solid began to precipitate, the precipitate
of 3a was filtered off, and the filtrate was further
evaporated, The precipitate of 2a was filtered off.
Yield 0.126 g (77%), colorless crystals, mp 273–274°C
1
13
The H and C NMR spectra were recorded on
a Bruker Avance III HD 400 spectrometer from solu-
tions in DMSO-d using hexamethyldisiloxane as
6
internal standard. The IR spectra were recorded on
a Perkin Elmer Spectrum Two spectrometer from
samples dispersed in mineral oil. The elemental
analyses were obtained with a Vario MICRO cube
analyzer. The reaction conditions were optimized by
UPLC using a Waters Acquity UPLC I-Class chro-
matograph equipped with an Acquity UPLC BEH C18
column (grain size 1.7 μm, eluent acetonitrile–water,
flow rate 0.6 mL/min), Acquity UPLC PDA eλ detec-
–
1
(decomp., from dioxane). IR spectrum, ν, cm :
1
3136 br (NH), 1774, 1705 (C=O). H NMR spectrum,
δ, ppm: 7.11 m (2H, Harom), 7.19 m (1H, Harom), 7.25 m
1
3
(1H, Harom), 11.85 br.s (1H, NH). C NMR spectrum,
Scheme 3.
O
O
S
R
NH2
S
R
N
+
H
2
N
NH
2
OR'
N
N
O
N
H
H
O
O
N
H
4
a–4g
3a–3g
3
, 4, R = Ph, R′ = Me (a), R = C
H
6 4
6 4 6 4
OEt-4, R′ = Me (b), R = C H Cl-4, R′ = Me (c), R = C H Br-4, R′ = Me (d),
R = C OMe-4, R′ = Me (e), R = C H
6
H
4
6 4
Me-4, R′ = Me (f), R = OEt, R′ = Et (g).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 7 2019

1
016
KOBELEV et al.
δ , ppm: 115.5, 116.2, 123.0, 124.7, 125.4, 140.4
(2H, CH ), 6.51 br.s (2H, NH ), 7.07 m (2H, Harom),
8.00 m (2H, Harom), 13.98 br.s (1H, N H). C NMR
C
2
2
3
2
2
13
(
Carom), 150.6 (C ), 153.7 (C ). Found, %: C 58.92;
H 3.11; N 8.57. C H NO . Calculated, %: C 58.90;
spectrum, δ , ppm: 14.4 (Me), 40.0 (CH ), 63.7
8
5
3
C
2
6
H 3.09; N 8.59.
Compound 2b was synthesized in a similar way.
-Chloro-2H-1,4-benzoxazine-2,3(4H)-dione
2b). Yield 0.150 g (76%), colorless crystals, mp 308–
(OCH
48.4 (C ), 162.9 (C ), 168.8 (C ), 193.4 (ArCO).
Found, %: C 50.99; H 4.63; N 18.30. C H N O S.
2
), 114.4 (2C), 128.7, 130.7 (2C), 144.2 (C ),
5
4'
3
1
1
3
14
4
3
6
Calculated, %: C 50.97; H 4.61; N 18.29.
(
3
3
–
1
4-Amino-6-[2-(4-chlorophenyl)-2-oxoethyl]-3-
sulfanylidene-3,4-dihydro-1,2,4-triazin-5(2H)-one
10°C (decomp., from dioxane). IR spectrum, ν, cm :
1
086 br (NH), 1781, 1714 (C=O). H NMR spectrum,
(
3c). Yield 0.214 g (72%, a), 0.220 g (74%, b); yellow
δ, ppm: 7.08 m (1H, Harom), 7.14 m (1H, Harom), 7.28 m
1
3
powder, mp 220–222°C (decomp.). IR spectrum, ν,
(
1H, Harom), 11.90 br.s (1H, NH). C NMR spectrum,
–
1
5
cm : 3200 br (N–H), 1679 (C=S, C =O), 1667
δ , ppm: 114.8, 117.8, 122.5, 126.9, 128.3, 139.5
C
1
3
2
(ArC=O). H NMR spectrum, δ, ppm: 4.40 s (2H,
(
Carom), 150.5 (C ), 153.2 (C ). Found, %: C 46.62;
CH ), 6.51 br.s (2H, NH ), 7.64 m (2H, Harom), 8.05 m
2
2
H 2.05; N 7.07. C H ClNO . Calculated, %: C 46.63;
8
4
3
2
13
(
2H, Harom), 14.01 br.s (1H, N H). C NMR spectrum,
H 2.04; N 7.09.
δ , ppm: 40.5 (CH ), 128.9 (2C), 130.2 (2C), 134.6,
C
2
4
-Amino-6-(2-oxo-2-phenylethyl)-3-sulfanyli-
6
5
3
1
38.7 (Carom), 143.7 (C ), 148.3 (C ), 168.8 (C ), 194.3
ArCO). Found, %: C 44.55; H 3.09; N 18.86.
C H ClN O S. Calculated, %: C 44.53; H 3.06;
dene-3,4-dihydro-1,2,4-triazin-5(2H)-one (3a).
a. Thiocarbonohydrazide, 0.106 g (1.0 mmol), was
added to a solution of 0.319 g (1.0 mmol) of 1a in
(
1
1
9
4
2
N 18.88.
-Amino-6-[2-(4-bromophenyl)-2-oxoethyl]-
-sulfanylidene-3,4-dihydro-1,2,4-triazin-5(2H)-one
3d). Yield 0.249 g (73%, a), 0.252 g (74%, b); yellow
powder, mp 198–200°C (decomp.). IR spectrum, ν,
1
5 mL of anhydrous dioxane, and the mixture was
4
refluxed for 1–3 min until the violet color typical of 1a
disappeared. The mixture was cooled and partly
evaporated until a solid began to precipitate, and the
precipitate of 3a was filtered off. Yield 0.191 g (73%),
yellow powder, mp 178–180°C (decomp., from EtOH).
3
(
–
1
5
cm : 3197 br (N–H), 1679 (C=S, C =O), 1661
(
1
ArC=O). H NMR spectrum, δ, ppm: 4.39 s (2H,
b. A solution of 0.106 g (1.0 mmol) of thiocarbono-
hydrazide was added to a solution of 0.206 g
CH ), 6.51 br.s (2H, NH ), 7.79 m (2H, Harom), 7.97 m
2
2
2
13
(
2H, Harom), 14.01 br.s (1H, N H). C NMR spectrum,
(
1.0 mmol) of methyl 4-phenyl-2,4-dioxobutanoate
δ , ppm: 40.4 (CH ), 127.9, 130.3 (2C), 131.9 (2C),
C
2
6
5
3
(4a) in 15 mL of ethanol. The mixture was refluxed for
1
34.6 (Carom), 143.7 (C ), 148.3 (C ), 168.8 (C ), 194.5
ArCO). Found, %: C 38.73; H 2.69; N 16.46.
C H BrN O S. Calculated, %: C 38.72; H 2.66;
1
.5 h and cooled, and the precipitate was filtered off.
(
Yield 0.197 g (75%), mp 178–180°C (decomp., from
1
1
9
4
2
–
1
EtOH). IR spectrum, ν, cm : 3196 br (N–H), 1698
N 16.42.
-Amino-6-[2-(4-methoxyphenyl)-2-oxoethyl]-
-sulfanylidene-3,4-dihydro-1,2,4-triazin-5(2H)-one
3e). Yield 0.208 g (71%, a), 0.216 g (74%, b); yellow
powder, mp 187–189°C (decomp.). IR spectrum, ν,
5
1
(
C=S, C =O), 1677 (PhC=O). H NMR spectrum, δ,
4
ppm: 4.41 s (2H, CH ), 6.52 br.s (2H, NH ), 7.58 m
2
2
3
(
(
1
4
2H, Harom), 7.70 m (1H, Harom), 8.04 m (2H, Harom),
2
13
4.01 br.s (1H, N H). C NMR spectrum, δ , ppm:
C
0.4 (CH ), 128.3 (2C), 128.8 (2C), 133.7, 135.9
–1
5
2
cm : 3217 br (N–H), 1661 (C=S, C =O), 1650
(
6
5
3
(
Carom), 143.9 (C ), 148.4 (C ), 168.3 (C ), 195.2
1
ArC=O). H NMR spectrum, δ, ppm: 3.87 (3H,
(
PhCO). Found, %: C 50.39; H 3.87; N 21.34.
OCH ), 4.34 s (2H, CH ), 6.51 br.s (2H, NH ), 7.08 m
3
2
2
C H N O S. Calculated, %: C 50.37; H 3.84; N 21.36.
2
11
10
4
2
(
2H, Harom), 8.01 m (2H, Harom), 13.98 br.s (1H, N H).
1
3
Compounds 3b–3g were synthesized in a similar
way.
C NMR spectrum, δ
(OCH ), 114.0 (2C), 128.9, 130.7 (2C), 144.2 (C ),
48.4 (C ), 163.6 (C ), 168.8 (C ), 194.5 (ArCO).
Found, %: C 49.33; H 4.17; N 19.16. C H N O S.
, ppm: 40.1 (CH ), 55.6
C 2
6
3
5
4′
3
1
4
-Amino-6-[2-(4-ethoxyphenyl)-2-oxoethyl]-
1
2
12
4
3
3
-sulfanylidene-3,4-dihydro-1,2,4-triazin-5(2H)-one
3b). Yield 0.229 g (75%, a), 0.236 g (77%, b); yellow
powder, mp 179–181°C (decomp., from EtOH). IR
Calculated, %: C 49.31; H 4.14; N 19.17.
(
4-Amino-6-[2-(4-methylphenyl)-2-oxoethyl]-
3-sulfanylidene-3,4-dihydro-1,2,4-triazin-5(2H)-one
(3f). Yield 0.169 g (61%, a), 0.171 g (62%, b); yellow
powder, mp 208–210°C (decomp.). IR spectrum, ν,
–
1
5
spectrum, ν, cm : 3226 br (N–H), 1665 (C=S, C =O),
1
1
648 (ArC=O). H NMR spectrum, δ, ppm: 1.37 t (3H,
Me, J = 7.0 Hz), 4.16 q (2H, OCH , J = 7.0 Hz), 4.33 s
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 7 2019

CLEAVAGE OF PYRROLO[2,1-c][1,4]BENZOXAZINE-1,2,4-TRIONES
1017
–
1
5
cm : 3226 br (N–H), 1728 (C=S, C =O), 1667
Compound 3a. The data were obtained from
a 0.36×0.10×0.10-mm yellow single crystal. Mono-
1
(
ArC=O). H NMR spectrum, δ, ppm: 2.41 (3H, CH ),
3
4
.37 s (2H, CH ), 6.51 br.s (2H, NH ), 7.37 m (2H,
arom), 7.93 m (2H, Harom), 14.00 br.s (1H, N H).
clinic crystal system, space group P2 /n; unit cell
2
2
1
2
H
parameters: a = 13.319(5), b = 8.9918(16), c =
1
3
3
C NMR spectrum, δ , ppm: 21.2 (CH ), 40.3 (CH ),
13.640(4) Å; β = 117.21(4)°; V = 1452.7(9) Å ; Z = 4.
C
3
2
1
28.4 (2C), 129.4 (2C), 133.5, 144.0 (Carom), 144.2
Final divergence factors: R = 0.0560, wR = 0.1381
1
2
6
5
3
(
C ), 148.4 (C ), 168.8 (C ), 194.7 (ArCO). Found, %:
for 2297 reflections with I > 2σ(I)]; R = 0.0889, wR =
1 2
C 52.14; H 4.39; N 20.26. C H N O S. Calculated,
0.1671 for all 3542 independent reflections; goodness
12
12
4
2
%: C 52.16; H 4.38; N 20.28.
of fit S = 1.031.
Ethyl 2-(4-amino-5-oxo-3-sulfanylidene-2,3,4,5-
The complete sets of X-ray diffraction data for
compounds 2a and 3a were deposited to the
Cambridge Crystallographic Data Centre [CCDC entry
nos. 1901530 (2a), 1901531 (3a)] and are available at
www.ccdc.cam.ac.uk.
tetrahydro-1,2,4-triazin-6-yl)acetate (3g). a. A mix-
ture of 0.188 g (1.0 mmol) of diethyl 2-oxobutane-
dioate (4g) and 0.106 g (1.0 mmol) of thiocarbonohy-
drazide was refluxed for 1.5 h. The mixture was cooled
and evaporated to dryness, the residue was ground
with ethanol, and the precipitate was filtered off. Yield
FUNDING
0
.166 g (72%, a), 0.173 g (75%, b); white powder,
–
1
This study was performed under financial support
by the Ministry of Science and Higher Education of
the Russian Federation (project no. 4.6774.2017/8.9)
and by the Government of Perm Krai.
mp 130–133°C (decomp.). IR spectrum, ν, cm : 3322,
3
ester). H NMR spectrum, δ, ppm: 1.19 t (3H,
OCH CH , J = 7.1 Hz), 3.65 (2H, CH ), 4.11 q (2H,
5
230 (N–H), 1735, 1667 (C=S, C =O), 1602 (C=O,
1
2
3
2
OCH , J = 7.1 Hz), 6.51 br.s (2H, NH ), 13.98 br.s
2
2
2
13
CONFLICT OF INTERESTS
(
(
1
1H, N H). C NMR spectrum, δ , ppm: 13.9
C
6
OCH CH ), 36.1 (CH ), 60.7 (OCH ), 142.2 (C ),
2
3
2
2
5
3
The authors declare the absence of conflict of
interests.
48.2 (C ), 168.3 (COOEt), 193.4 (C ). Found, %:
C 36.53; H 4.37; N 20.83. C H N O S. Calculated, %:
7
10
4
3
C 36.52; H 4.38; N 20.85.
REFERENCES
X-Ray analysis of compounds 2a and 3a. The
X-ray diffraction data were obtained on an Xcalibur
Ruby single-crystal diffractometer with a CCD detec-
1
. Kollenz, G., Justus Liebigs Ann. Chem., 1972, vol. 762,
p. 13. doi 10.1002/jlac.19727620103.
tor according to standard procedure [Mo K radiation,
α
2. Mikhailovskii, A.G., Shklyaev, V.S., and Aleksand-
rov, B.B., Chem. Heterocycl. Compd., 1990, vol. 26,
p. 674. doi 10.1007/BF00756422
temperature 295(2) K, ω-scanning with a step of 1°].
A correction for absorption was applied by SCALE3
ABSPACK algorithm [19]. The structures were solved
3. Mashevskaya, I.V., Makhmudov, R.R., Aleksandro-
va, G.A., Golovnina, O.V., Duvalov, A.V., and Masli-
vets, A.N., Pharm. Chem. J., 2001, vol. 35, p. 196. doi
2
using Superflip [20] and were refined against F by the
full-matrix least-squares method in anisotropic approx-
imation for all non-hydrogen atoms using SHELXL-
1
0.1023/A:1010475811489
4
5
6
7
. Bozdyreva, K.S. and Maslivets, A.N., Russ. J. Org.
Chem., 2006, vol. 42, p. 463. doi 10.1134/
s1070428006030249
2
014 [21] with OLEX2 graphical interface [22]. The
positions of hydrogen atoms were refined according to
the riding model (except for NH and NH hydrogen
atoms which were refined independently in isotropic
approximation).
2
. Denislamova, E.S. and Maslivets, A.N., Russ. J. Org.
Chem., 2010, vol. 46, p. 389. doi 10.1134/
s1070428010030152
Compound 2a. The data were obtained from
a 0.54×0.14×0.04-mm colorless single crystal. Mono-
clinic crystal system, space group Pn; unit cell param-
eters: a = 5.139(2), b = 11.703(5), c = 5.826(2) Å; β =
1
. Mashevskaya, I.V., Suchkova, N.V., Kuslina, L.V., and
Maslivets, A.N., Russ. J. Org. Chem., 2015, vol. 51,
p. 1301. doi 10.1134/s1070428015090158
. Dubovtsev, A.Yu., Dmitriev, M.V., Maslivets, A.N., and
Rubin, M., Beilstein J. Org. Chem., 2017, vol. 13,
p. 2179. doi 10.3762/bjoc.13.218
3
00.33(4)°; V = 344.7(2) Å ; Z = 2. Final divergence
factors: R = 0.0443, wR = 0.1146 for 889 reflections
1
2
with I > 2σ(I)]; R = 0.0539, wR = 0.1273 for all
8. Kurzer, F. and Wilkinson, M., Chem. Rev., 1970, vol. 70,
1
2
1
073 independent reflections; goodness of fit S = 1.064.
p. 111. doi 10.1021/cr60263a004
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 7 2019

1
018
KOBELEV et al.
9. Ali, T.E., J. Sulfur Chem., 2009, vol. 30, p. 611. doi
16. Andreichikov, Yu.S., Kol’tsova, S.V., Zhikina, I.A., and
1
0.1080/17415990902894265
Nekrasov, D.D., Russ. J. Org. Chem., 1999, vol. 35,
1
0. Wang, Q., Yang, Ya., Liu, Yu., and Wang, Z., CN Patent
no. 107266380, 2017.
p. 1538.
1
1
7. Anastas, P.T. and Kirchhoff, M.M., Acc. Chem. Res.,
11. Hamama. W.S., Ibrahim, M.E., Ghaith, E.A., and
2002, vol. 35, p. 686. doi 10.1021/ar010065m.
Zoorob, H.H., Synth. Commun., 2017, vol. 47, p. 566.
doi 10.1080/00397911.2016.1276190
8. Alfonsi, K., Colberg, J., Dunn, P.J., Fevig, T.,
Jennings, S., Johnson, T.A., Kleine, H.P., Knight, C.,
Nagy, M.A., Perry, D.A., and Stefaniak, M., Green
Chem., 2008, vol. 10, p. 31. doi 10.1039/B711717E
1
1
2. Gao, J., Midde, N., Zhu, J., Terry, A.V., McInnes, C.,
and Chapman, J.M., Bioorg. Med. Chem. Lett., 2016,
vol. 26, p. 5573. doi 10.1016/j.bmcl.2016.09.072
3. Gangarapu, K., Manda, S., Jallapally, A., Thota, S.,
Karki, S.S., Balzarini, J., Clercq, E., and Tokuda, H.,
Med. Chem. Res., 2014, vol. 23, p. 1046. doi 10.1007/
s00044-013-0684-3
1
2
2
9. CrysAlisPro, Version 1.171.37.33 (release 27-03-2014
CrysAlis171 .NET), AgilentTechnologies.
0. Palatinus, L. and Chapuis, G., J. Appl. Crystallogr.,
2
007, vol. 40, p. 786. doi 10.1107/S0021889807007637
1. Sheldrick, G.M., Acta Crystallogr., Sect. C, 2015,
1
1
4. Kobelev, A.I., Stepanova, E.E., and Maslivets, A.N.,
vol. 71, p. 3. doi 10.1107/S2053273314026370
Russ. J. Org. Chem., 2018, vol. 54, p. 1270. doi
1
0.1134/s1070428018050159
22. Dolomanov, O.V., Bourhis, L.J., Gildea, R.J.,
Howard, J.A.K., and Puschmann, H., J. Appl.
Crystallogr., 2009, vol. 42, p. 339. doi 10.1107/
S0021889808042726
5. Konovalova, V. and Maslivets, A., Mini-Rev. Org.
Chem., 2018, vol. 15, p. 1. doi 10.2174/
1
570193X15666180712115204
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 7 2019