2,2′,2″-(2,4,6-Trioxo-1,3,5-triazinane-1,3,5-triyl)triacetic Acid Derivatives. New Aspects of Reactivity

Article abstract of DOI:10.1134/S1070428020060135

Abstract: Reaction of 2,2′,2″-(2,4,6-trioxo-1,3,5-triazinane-1,3,5-triyl)triacetic acid derivatives with nucleophiles in aqueous medium involved opening of the triazinane ring with elimination of carbonyl group, followed by recyclization to 1-carbamoylhydantoins.

Full text of DOI:10.1134/S1070428020060135

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 6, pp. 1046–1053. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Organicheskoi Khimii, 2020, Vol. 56, No. 6, pp. 947–956.
2,2′,2″-(2,4,6-Trioxo-1,3,5-triazinane-1,3,5-triyl)triacetic Acid
Derivatives. New Aspects of Reactivity
M. A. Kavinaa,b and V. V. Sizova,*
a CHEM Ltd. Scientific and Production Company, Kuz’molovskii, Leningrad oblast, 188663 Russia
b St. Petersburg State Chemical Pharmaceutical University, St. Petersburg, 197022 Russia
*e-mail: vvsizov@list.ru
Received January 23, 2020; revised February 1, 2020; accepted February 3, 2020
Abstract—Reaction of 2,2′,2″-(2,4,6-trioxo-1,3,5-triazinane-1,3,5-triyl)triacetic acid derivatives with nucleo-
philes in aqueous medium involved opening of the triazinane ring with elimination of carbonyl group, followed
by recyclization to 1-carbamoylhydantoins.
Keywords: cyanuric acid, chloroacetamide, ethyl chloroacetate, hydantoin, urea, 1-carbamoylhydantoin
DOI: 10.1134/S1070428020060135
In the preceding communication [1] we described
a procedure for the synthesis of 2-chloro-6,7-dihydro-
5H-pyrrolo[1,2-a]imidazoles by dehydration of
2-(2-oxopyrrolidin-1-yl)acetamides with phosphoryl
chloride [1]. With the goal of extending the proposed
procedure to the synthesis of other fused imidazoles, in
this work we tried to accomplish a similar transforma-
tion of another N-acylglycinamide derivative,
2,2′,2″-(2,4,6-trioxo-1,3,5-triazinane-1,3,5-triyl)triacet-
amide (2a) (Scheme 1).
The alkylation of cyanuric acid with chloroaceto-
nitrile in DMF in the presence of triethylamine was
described in [9]. Triethyl ester 2b was synthesized by
reaction of ethyl chloroacetate with potassium cyanate
at 150–160°C [8]. Published data on the reactivity of
2,2′,2″-(2,4,6-trioxo-1,3,5-triazinane-1,3,5-triyl)triace-
tic acid derivatives are limited to hydrolysis of cyano
groups to amide [9] or carboxy [5], hydrolysis of amide
groups to carboxy [5, 8], esterification of carboxy
groups to ester, and aminolysis of the latter [4, 6, 10].
Tris(tetrazol-5-ylmethyl) isocyanurate was obtained by
reacting the trinitrile with sodium azide in DMF at
140°C [11].
The synthesis and reactivity of 2,2′,2″-(2,4,6-trioxo-
1,3,5-triazinane-1,3,5-triyl)triacetic acid derivatives
have been the subject of a few studies. In most cases,
these compounds are synthesized by alkylation of
cyanuric acid trisodium salt with 2-haloacetic acid
derivatives on heating in a solvent or under solvent-
free conditions at 190–195°C [2–8]. Dimethylform-
amide (DMF), hexamethylphosphoramide (HMPA), or
N-methylpyrrolidone (NMP) were used as solvents.
We have synthesized triamide 2a and triester 2b
accoring to a modified procedure, by reacting cyanuric
acid trisodium salt with chloroacetamide and ethyl
chloroacetate in DMF (Scheme 1).
We failed to obtain 2,6,10-trichlorotriimidazo-
[1,2-a:1′,2′-c:1″,2″-e][1,3,5]triazine (3) by treatment of
Scheme 1.
O
N
Na+
R
O
O
N
O
O
N
O
ClCH2C(O)R, DMF
O
O
Na+ –N
N– Na+
N
R
R
O
1
2a, 2b
R = NH2 (a), OEt (b).
1046

2,2′,2″-(2,4,6-TRIOXO-1,3,5-TRIAZINANE-1,3,5-TRIYL)TRIACETIC ACID DERIVATIVES.
1047
Scheme 2.
Cl
N
N
N
O
N
N
N
N
NH2
O
Cl
Cl
POCl3 or PCl5
3
O
N
O
O
N
O
N
O
N
Cl
H2N
NH2
O
O
N
O
N
2a
+
N
N
N
N
N
N
N
N
O
Cl
O
Cl
4
5
2a with phosphoryl chloride on heating. The reaction
under more severe conditions using phosphorus penta-
chloride as dehydrating agent was also unsuccessful,
and no compound 3 was formed. Instead, we isolated
the corresponding trinitrile 4 and 2,2′,2″-(2,4,6-trioxo-
1,3,5-triazinane-1,3,5-triyl)tris(2-chloroacetonitrile)
(5) in 5 and 48% yields, respectively (Scheme 2). Com-
pound 5 is unstable, and it slowly decomposes on
exposure to air.
unexpected result. When a suspension of 2b in 25%
aqueous ammonia (15 mL of 25% ammonia solution
per gram of 2b) was stirred at room temperature, a so-
lution was formed after 7–10 h. Assumingly, evapora-
tion of this solution under reduced pressure was accom-
panied by cyclization of intermediate compound A,
and the white crystalline product consisted mainly of
hydantoin 8 (95%) and urea 9 (5%). The yield of
mixture 8/9 was 75% based on the initial triester 2b
(Scheme 5). We failed to isolate intermediate product
A in the pure state. Pure compound 8 can be isolated
recrystallization in DMF where urea 9 is insoluble. The
ratio of products 8 and 9 in the reaction mixture
depended on the reaction time. After 20 days at room
temperature, the ratio 8/9 changed to the opposite, and
urea 9 was the only product after 21–25 days (Fig. 1).
Unexpectedly, by heating a suspension of 5 in water
we obtained 43% of 5-hydroxy-2,4-dioxoimidazoli-
dine-1-carboxamide (6) (Scheme 3). The reaction of 5
with some aromatic amines led to the formation of only
symmetrical ureas 7c–7e (Scheme 4).
An attempt to synthesize triamide 2a by the ammo-
nolysis of triester 2b in aqueous ammonia also gave
Scheme 3.
O
N
O
HO
N
HO
OH
OH
O
9H2O
H2O
O
N
O
O
N
O
5
O
O
O
O
–3NH4Cl
–CO2
NH HN
HO
OH
HO
OH
OH
OH
OH
OH
O
O
O
HO
H2O
–2OCHCOOH
OH
O
H2N
N
NH
–H2O
O
N
HO
O
NH2 NH2
6
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

KAVINA, SIZOV
1048
Scheme 4.
R
R
RC6H4NH2, xylene
O
5
N
H
N
H
7c–7e
R = 2-Me (c), 4-Br (d), 3-MeOC(O) (e).
Scheme 5.
O
O
H2N
NH2
H
N
O
O
O
N
NH3
H2O
O
N
O
2a, 2b
–HOCN
NH
O
O
NH
N
NH2
O
NH2
H2N
H2N
NH2
O
A
O
O
O
O
H
N
NH2
N
N
+
H2N
H2N
N
N
H
N
H
NH2
–NH3
H
O
O
O
O
O
O
8
9
O
O
H
N
NH3
NH2
8
9
H2N
N
N
H
–HOCN
O
O
NH2
Scheme 6.
O
H
N
H
N
MeNH2, H2O
2b, 8
Me
N
H
N
H
Me
O
O
10
Scheme 7.
O
O
N
N
H2N
NaOH/H2O or NH3/H2O or MeNH2/H2O
N
H
NH2
2a, 4
O
O
O
8
O
O
OEt
O
O
N
O
H
N
MeNH2/H2O
H
N
O
O
N
N
N
H
Me
N
N
Me
O
EtO
OEt
O
O
O
2b
11
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

2,2′,2″-(2,4,6-TRIOXO-1,3,5-TRIAZINANE-1,3,5-TRIYL)TRIACETIC ACID DERIVATIVES.
1049
Scheme 8.
O
N
O
O– Na+
O– Na+
NaOH/H2O
–NH3
NaOH
O
N
O
O
O
O
N
O
O
2a, 4
O
O
N
NH
O
N
H2N
NH2
O
H2N
NH2
O– Na+
O– Na+
NaOH
H+
8
O
N
O
–Na2CO3
–H2O
O
O
NH HN
H2N
NH2
However, the yield of 9 was as low as 47%, which
indicated significant contribution of decomposition
processes. Urea 9 was also formed when a mixture of 8
and aqueous ammonia was stirred for a long time at
room temperature.
ring in 4 by the action of ammonia or methylamine was
accompanied by hydrolysis of the cyano groups to
amide, and analogous reactions with 2b were accom-
panied by aminolysis of the ester groups.
Thus, successful opening of the triazinane ring,
which leads to the formation of soluble linear inter-
mediate, requires a certain excess of the nucleophile. In
the reactions with 20–30% aqueous solutions of amines
in an amount of 15 mL and more per gram of the
substrate, the reaction mixture contains a large excess
of the nucleophile, and its further increase does not
favor side processes. In the reaction with alkali, 3 equiv
of the nucleophile is necessary to achieve successful
triazinane ring opening. If the amount of alkali is
smaller, the dissolution process does not go to com-
pletion, and the yield of 1-carbamoylhyidantoin 8
sharply decreases. The use of a larger amount of alkali
A similar transformation of triamide 2a required
much longer time: the initial compound dissolved com-
pletely after 44–48 h, and a mixture of 8 and 9 at the
same ratio was isolated in 66% yield. Prolonged
treatment of trieester 2b, as well as hydantoin 8, with
aqueous methylamine under similar conditions
afforded symmetrical urea 10 as the only product
(Scheme 6).
The results of our studies showed that opening of
the triazinane ring in 2,2′,2″-(2,4,6-trioxo-1,3,5-triazi-
nane-1,3,5-triyl)triacetic acid derivatives, followed by
cyclization to the corresponding 1-carbamoylhydantoin,
has a general character and that these processes occur
by the action of both ammonia and other nucleophiles
(Scheme 7).
c9, wt %
90
80
In practice, compounds 2a, 2b, and 4 were con-
verted to 8 and 11 by stirring a suspension of the initial
reactant in an aqueous solution of a nucleophile until
a solution containing acyclic intermediate compound
was formed, and the resulting solution was acidified to
promote recyclization. We found that increase of the
amount of amine solution with respect to the substrate
accelerated triazinane ring opening and reduced the
amount of open-chain by-products. In the reactions of
2a, 2b, and 4 with 25% aqueous ammonia using 30 mL
of the latter per gram of the former, the initial com-
pound dissolved in 1–3 h, and the cyclization product
contained no impurity of 9. Opening of the triazinane
70
60
50
40
30
20
10
0
0
2
4
6
8
10 12 14 16 18 20
Reaction time, days
Fig. 1. Change of the concentration of compound 9 in the
reaction mixture with time.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

KAVINA, SIZOV
1050
Scheme 9.
H2N
O
O
N
NH
H
N
NH2
NH2
O
N
H
O
N
N2H4·H2O
N2H4
O
N
O
2a, 2b, 4
O
O
O
HN
NH
N
–EtOH
H2N
N
NH2
H2N
NH
N
H
N
H
HN
N
H
N
NH2
O
NH2
H
N
H2N
O
NH
HN
NH2
H
N
O
N
NH2
H2O
–H2NCH2C(O)NHNH2
N2H4
–(H2NNH)2C=O
HN
NH
O
O
O
O
HN
NH
O
O
H2N
NH
H2N
NH
12
N
H
N
H
O
inevitably promotes decomposition processes which
become dominating.
and filtered while hot. The filtrate was evaporated to
dryness under reduced pressure, the residue was dis-
persed in 1 L of ethanol, the suspension was stirred for
1 h, and the precipitate was filtered off, washed with
ethanol, and dried at 80°C. Yield 185 g (93%), white
crystals.
The fact that 3 equiv of alkali is necessary indicates
that the reaction involves hydrolysis of one amide or
nitrile group to carboxy. Probably, this step is the first
one and rate-determining, since no complete dissolution
of the initial compound was observed in the presence of
2 equiv of alkali (Scheme 8).
Compounds 2a and 2b (general procedure). Salt 1,
0.75 mol, was dispersed in 800 mL of DMF, 2.45 mol
of chloroacetamide or ethyl chloroacetate was added,
and the mixture was heated to 100°C and stirred for
72–80 h at that temperature.
No expected 1-carbamoylhydantoin was formed
when amide 2a, triester 2b, or trinitrile 4 was treated
with 25% aqueous hydrazine, and the major product
(yieldom 30–50%) was unstable open-chain derivative
12 (Scheme 9) which decomposed on attempted
recrystallization from water and organic solvents.
2,2′,2″-(2,4,6-Trioxo-1,3,5-triazinane-1,3,5-triyl)-
triacetamide (2a). The mixture was cooled to room
temperature, and the precipitate was filtered off,
washed with DMF, and dispersed in 1 L of water. The
suspension was stirred for 0.5 h, and the product was
filtered off, washed with water and acetone, and dried
at 80°C. Yield 88%, white powder, mp 350–352°C
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
1
(mp 350–351°C [6]). H NMR spectrum (DMSO-d6),
Avance III UltraShield Plus spectrometer (400 MHz).
HPLC/MS data were obtained with a Thermo Scientific
Fisher TSQ Quantum Access MAX instrument.
Elemental analyses were carried out on a Thermo
Scientific FLASH 2000 CHNS analyzer. The melting
points were measured using an electrically heated
melting point apparatus with a measurement range of
20–360°C.
δ, ppm: 4.31 s (2H, CH2), 7.24 s (1H, NH2), 7.59 s (1H,
NH2). 13C NMR spectrum (DMSO-d6), δC, ppm: 44.78
(CH2), 149.11 (CO), 168.15 (CONH2).
Triethyl 2,2′,2″-(2,4,6-trioxo-1,3,5-triazinane-
1,3,5-triyl)triacetate (2b). The mixture was cooled to
room temperature and slowly poured into 1,5 L of cold
water. The resulting suspension of the granular product
was vigorously stirred at 25°C for 2–3 h to make it
uniform, and the precipitate was filtered off, washed
with water and 50% aqueous isopropyl alcohol, and
dried in air. Yield 92%, colorless prisms, mp 64–65°C
Cyanuric acid trisodium salt (1). A solution of
125 g (3.1 mol) of sodium hydroxide in 500 mL of
water was added to a suspension of 129 g (1 mol) of
cyanuric acid in 1.5 L of water. The mixture was heated
until it became homogeneous, treated with charcoal,
1
(from i-PrOH) (mp 75°C [2]). H NMR spectrum
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

2,2′,2″-(2,4,6-TRIOXO-1,3,5-TRIAZINANE-1,3,5-TRIYL)TRIACETIC ACID DERIVATIVES.
1051
(DMSO-d6), δ, ppm: 1.21 t (3H, CH3, J = 8.0 Hz),
4.16 q (2H, CH2, J = 4.0, 8.0 Hz), 4.59 s (2H, CH2).
13C NMR spectrum (DMSO-d6), δC, ppm: 14.37 (CH3),
43.95 (CH2), 61.89 (CH2), 148.51 (CO), 167.42
(COOEt).
Compounds 7c–7e (general procedure). Compound
5, 1 g (2.86 mmol), was added to a solution of
25.5 mmol of o-toluidine, p-bromoaniline, or methyl
3-aminobenzoate in 25–30 mL of o-xylene. The mix-
ture was heated to 130°C, stirred for 3 h at that tem-
perature, and cooled to room temperature, and the
precipitate was filtered off.
2,2′,2″-(2,4,6-Trioxo-1,3,5-triazinane-1,3,5-triyl)-
triacetonitrile (4) and 2,2′,2″-(2,4,6-trioxo-1,3,5-tri-
azinane-1,3,5-triyl)tris(chloroacetonitrile) (5). A sus-
pension of 41.7 g (0.14 mol) of compound 2a in
100 mL of phosphoryl chloride was heated to 40–45°C,
and 200 g (0.96 mol) of phosphorus pentachloride was
added over a period of 2 h. The mixture was heated for
2 h at 40°C to 70°C so that to control the rate of
evolution of hydrogen chloride. The mixture was then
stirred at 70–75°C for 16–18 h, and the resulting sus-
pension was cooled to room temperature. The precip-
itate was filtered off and washed with water and
ethanol. Yield of 4 1.7 g (5%), colorless prisms,
N,N′-Bis(2-methylphenyl)urea (7c). The product
was washed with ethanol on a filter, dispersed in hot
water, filtered off, and washed with water and acetone.
Yield 0.43 g (62%), light violet prisms, mp 246–247°C
1
(from i-PrOH). H NMR spectrum (DMSO-d6), δ,
ppm: 2.27 s (3H, CH3), 6.95 t (1H, Harom, J = 8.0 Hz),
7.12–7.19 m (2H, Harom), 7.80 d (1H, Harom, J =
4.0 Hz), 8.24 s (1H, NH). 13C NMR spectrum
(DMSO-d6), δC, ppm: 18.51 (CH3), 121.94 (CHarom),
123.14 (CHarom), 126.56 (CHarom), 128.20 (CHarom),
130.65 (Carom), 137.97 (Carom), 153.42 (CO).
Found, %: C 74.84; H 6.78; N 11.69. C15H16N2O.
Calculated, %: C 74.96; H 6.72; N 11.66.
1
mp 224–226°C (from MeCN). H NMR spectrum
(DMSO-d6): δ 4.90 ppm, s (CH2).
N,N′-Bis(4-bromophenyl)urea (7d). The product
was washed on a filter with ethanol and acetone, dis-
persed in hot water, filtered off, and washed with hot
water and acetone. Yield 0.54 g (51%), colorless
needles, mp 300–301°C (decomp., from DMF).
1H NMR spectrum (DMSO-d6), δ, ppm: 7.44 s (4H,
Harom), 9.01 s (1H, NH). 13C NMR spectrum
(DMSO-d6), δC, ppm: 113.84 (CHarom), 120.68 (2C,
CHarom), 131.99 (2C, CHarom), 139.43 (CHarom), 137.97
(Carom), 152.75 (CO). Found, %: C 42.14; H 2.82;
N 7.59. C13H10Br2N2O. Calculated, %: C 42.19;
H 2.73; N 7.57.
The filtrate was evaporated to dryness under
reduced pressure, and the residue was poured into
an ice–water mixture (0–5°C). The resulting suspension
was stirred for 1 h at 5–10°C, and the precipitate was
filtered off, washed with water, and dried in air. Yield
of 5 sostavil 23 g (48%), white powder, mp 185–189°C
(from toluene–acetone). 1H NMR spectrum (DMSO-d6):
δ 7.99 ppm, s (CH). 13C NMR spectrum (DMSO-d6):
δC, ppm: 49.61 (CH), 112.94 (CN), 144.34 (CO).
Found, %: C 30.85; H 0.74; N 24.01. C9H3Cl3N6O3.
Calculated, %: C 30.93; H 0.87; N 24.05.
5-Hydroxy-2,4-dioxoimidazolidine-1-carbox-
amide (6). Compound 5, 5 g (0.014 mol), was added in
portions with stirring over a period of 1 h to 25 mL of
water heated to 85–90°C, and the mixture was stirred
for 30 min more until it became homogeneous. The hot
solution was treated with charcoal and filtered, and the
filtrate was cooled to room temperature. The resulting
suspension was stirred for 2–3 h, and the precipitate
was filtered off and washed with water and acetone.
Yield 1 g (43%), colorless prisms, mp 219–220°C
Methyl 3-({[3-(methoxycarbonyl)phenyl]carba-
moyl}amino)benzoate (7e). The product was washed
with ethanol on a filter, dispersed in hot water, filtered
off, and washed with hot water and ethanol. Yield
0.45 g (48%), light brown prisms, mp 228–229°C
1
(from EtOH). H NMR spectrum (DMSO-d6), δ, ppm:
3.87 s (3H, CH3), 7.44 t (1H, Harom, J = 8.0 Hz), 7.59 d
(1H, Harom, J = 4.0 Hz), 7.65 d (1H, Harom, J = 4.0 Hz),
8.22 s (1H, Harom), 8.98 s (1H, NH). 13C NMR spec-
trum (DMSO-d6), δC, ppm: 52.65 (CH3), 119.22
(CHarom), 123.14 (CHarom), 123.42 (CHarom), 129.68
(CHarom), 130.64 (CHarom), 140.43 (CHarom), 152.95
(CO), 166.67 (COOCH3). Mass spectrum: m/z 329
(Irel 100%) [M + H]+. Found, %: C 62.11; H 4.98;
N 8.51. C17H16N2O5. Calculated, %: C 62.18; H 4.92;
N 8.53. M 328.32.
1
(decomp., from H2O). H NMR spectrum (DMSO-d6),
δ, ppm: 5.47 d (1H, CH, J = 4.0 Hz), 7.22 br.s (1H,
NH2), 7.33 d (OH, 1H, J = 4.0 Hz), 7.43 br.s (1H,
NH2), 11.42 br.s (1H, NH). 13C NMR spectrum
(DMSO-d6), δC, ppm: 77.98 (CH), 151.57 (CO),
155.58 (CO), 171.28 (CONH2). Mass spectrum:
m/z 158 (Irel 100%) [M – H]–. Found, %: C 30.08;
H 3.19; N 26.32. C4H5N3O4. Calculated, %: C 30.20;
H 3.17; N 26.41. M 159.10.
N,3-Bis(2-amino-2-oxoethyl)-2,4-dioxoimidazoli-
dine-1-carboxamide (8). Compound 2a or 2b,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

KAVINA, SIZOV
1052
0.13 mol, was dispersed in 750 mL of 25% aqueous
ammonia, and the mixture was stirred at room tempera-
ture until it became homogeneous (44–48 h in the
reaction with 2a or 7–10 h in the reaction with 2b). The
solution was treated with charcoal and filtered, and the
filtrate was evaporated to dryness under reduced
pressure. The residue was treated with hot ethanol, the
resulting suspension was cooled and stirred for 2–3 h,
and the precipitate was filtered off and washed with
ethanol on a filter. The product contained 5 wt % of 9.
To isolate pure compound 8, the product was dissolved
in DMF at 80°C, the solution was filtered from poorly
soluble compound 9, the filtrate was cooled, and the
precipitate was filtered off, washed with water and
acetone, and dried at 80°C. Yield 66% (from 2a), 75%
(from 2b); colorless prisms, mp 233–234°C (decomp.,
prisms, mp 224–225°C (decomp., from H2O). 1H NMR
spectrum (DMSO-d6), δ, ppm: 2.59 d (6H, CH3, J =
4.0 Hz), 3.59 d (4H, CH2), 6.40 t (2H, NH, J = 4.0 Hz),
7.74 br.s. (2H, NH). 13C NMR spectrum (DMSO-d6),
δC, ppm: 25.67 (CH3), 43.03 (CH2), 159.96 (CO),
173.46 (CO). Found, %: C 41.64; H 7.07; N 27.68.
C7H14N4O3. Calculated, %: C 41.58; H 6.98; N 27.71.
Synthesis of compound 8 by reaction of 2a, 2b, or
4 with aqueous ammonia (general procedure). Com-
pound 2a, 2b, or 4, 0.01 mol, was added at room tem-
perature to 75 mL of 25% aqueous ammonia, and the
mixture was stirred until it became homogeneous. The
solution was filtered, and the filtrate was kept under
reduced pressure (15–20 mm Hg) at 30–35°C for 20–
30 min. The residue was acidified to pH 3–4, heated to
50°C, and stirred for 2 h. The mixture was cooled to
5°C and kept for 16 h at that temperature, and the
precipitate was filtered off and washed with cold water
and acetone. Yield 72, 75, and 69% from 2a, 2b, and 4,
respectively.
1
from DMF). H NMR spectrum (DMSO-d6), δ, ppm:
3.82 d (2H, CH2, J = 4.0 Hz), 3.98 s (2H, CH2), 4.29 s
(2H, CH2), 7.18 s (1H, NH2), 7.33 s (1H, NH2), 7.48 s
(1H, NH2), 7.66 s (1H, NH2), 8.15 t (1H, NH, J =
4.0 Hz). 13C NMR spectrum (DMSO-d6), δC, ppm:
41.03 (CH2), 42.95 (CH2), 48.54 (CH2), 150.82 (CO),
155.35 (CO), 167.87 (CO), 168.80 (CONH2), 170.57
(CONH2). Mass spectrum: m/z 258 (Irel 100%)
[M + H]+. Found, %: C 37.38; H 4.39; N 27.20.
C8H11N5O5. Calculated, %: C 37.36; H 4.31; N 27.23.
M 257.20.
Synthesis of compound 8 by reaction of 2a or 4
with aqueous methylamine (general procedure).
Compound 2a, or 4, 0.01 mol, was added to 75 mL of
30% aqueous methylamine, and the mixture was stirred
at room temperature until it became homogeneous. The
solution was filtered, and the filtrate was kept under
reduced pressure (15–20 mm Hg) at 30–35°C for
30 min. The residue was acidified to pH 3–4, heated to
50°C, and stirred for 2 h. The mixture was cooled to
5°C and kept for 16 h at that temperature, and the
precipitate was filtered off and washed with cold water
and acetone. Yield 70% from 2a or 67% from 4.
N-(2-Amino-2-oxoethyl)-2-{[(2-amino-2-oxo-
ethyl)carbamoyl]amino}acetamide (9). A suspension
of 0.13 mol of compound 2a, 2b, or 8 in 750 mL of
25% aqueous ammonia was stirred at room temperature
for 21–25 days. The precipitate was filtered off and
washed with water and acetone. Yield 45–47%, white
1
Synthesis of compound 8 by reaction of 2a and 4
with aqueous sodium hydroxide (general procedure).
Compound 2a, or 4, 0.01 mol, was dispersed in 30 mL
of water, 0.03 mol of sodium hydroxide was added at
room temperature, and the mixture was stirred until
it became homogeneous (3–7 min). The solution was
filtered, and the filtrate was acidified to pH 3–4
(foaming occurred due to evolution of CO2), heated to
50°C, and stirred for 2 h. The mixture was cooled to
5°C and kept for 16 h at that temperature, and the
precipitate was filtered off and washed with cold water
and acetone. Yield 75% from 2a or 73% from 4.
powder, mp 234–235°C (decomp.) H NMR spectrum
(DMSO-d6), δ, ppm: 3.58–3.65 m (6H, CH2), 6.41 t
(1H, NH, J = 4.0 Hz), 6.49 t (1H, NH, J = 4.0 Hz),
7.01 s (1H, NH2), 7.06 s (1H, NH2), 7.27 d (2H, NH2,
J = 8.0 Hz), 8.04 t (1H, NH, J = 4.0 Hz). 13C NMR
spectrum (DMSO-d6), δC, ppm: 42.30 (CH2), 43.19
(CH2), 43.67 (CH2), 158.57 (CO), 170.83 (CO), 171.55
(CONH2), 172.45 (CONH2). Mass spectrum: m/z 232
(Irel 100%): [M + H]+. Found, %: C 36.28; H 5.72;
N 30.26. C7H13N5O4. Calculated, %: C 36.36; H 5.67;
N 30.29. M 231.21.
N-Methyl-2-({[2-(methylamino)-2-oxoethyl]car-
bamoyl}amino)acetamide (10). A suspension of
10 mmol of compound 2b or 8 in 50 mL of 30% aque-
ous methylamine was stirred at room temperature for
48 h. The resulting solution was filtered and evaporated
to dryness under reduced pressure, and the residue was
recrystallized from ethanol. Yield 68–71%. Colorless
N,3-Bis[2-(methylamino)-2-oxoethyl]-2,4-dioxo-
imidazolidine-1-carboxamide (11). A suspension of
2 g (0.005 mol) of compound 2b in 50 mL of
30% aqueous methylamine was stirred until it became
homogeneous (1–2 h). The solution was filtered, and
the filtrate was kept under reduced pressure (15–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020

2,2′,2″-(2,4,6-TRIOXO-1,3,5-TRIAZINANE-1,3,5-TRIYL)TRIACETIC ACID DERIVATIVES.
1053
20 mm Hg) at 30–35°C for 30 min. The residue was
acidified to pH 3–4, heated to 50°C, and stirred for 2 h.
The mixture was cooled to 5°C and kept for 16 h at that
temperature, and the precipitate was filtered off and
washed with cold water and acetone. Yield 68%,
colorless prisms, mp 242–243°C (from H2O). 1H NMR
spectrum (DMSO-d6), δ, ppm: 2.62 d (6H, CH3, J =
4.0 Hz), 3.82 d (2H, CH2, J = 4.0 Hz), 4.01 s (2H,
CH2), 4.30 s (2H, CH2), 7.93 br.s. (1H, NH), 8.11 br.s.
(1H, NH), 8.16 t (1H, NH, J = 8.0 Hz). 13C NMR
spectrum (DMSO-d6), δC, ppm: 25.93 (CH3), 25.98
(CH3), 41.23 (CH2), 43.19 (CH2), 48.58 (C5H2), 150.87
(CO), 155.30 (CO), 166.14 (CO), 168.74 and 168.93
(C2, C4). Found, %: C 42.02; H 5.60; N 24.47.
C10H15N5O5. Calculated, %: C 42.11; H 5.30; N 24.55.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
REFERENCES
1. Kavina, M.A., Sizov, V.V., and Yakovlev, I.P., Russ. J.
Org. Chem., 2018, vol. 54, p. 901.
https://doi.org/10.1134/S107042801806012X
2. Chiron-Charrier, M. and Caubere, P., Synth. Commun.,
1993, vol. 23, p. 2659.
https://doi.org/10.1080/00397919308013795
3. Frazier, T.C., Little, E.D., and Lloyd, B.E., J. Org.
Chem., 1960, vol. 25, p. 1944.
https://doi.org/10.1021/jo01081a029
4. Rasberger, M., Riehen, D.K., and Zofingen, F., FRG
Patent Appl. no. 2730397, 1978.
5. Spencer Chem. Co. UK Patent no. 988631, 1965.
6. Rebek, J., Jr., Berryman, O.B., and Sather, A.C., Int.
Patent Appl. no. WO 2010138720.
7. Bayat, Y. and Hajighasemali, F., Chem. Pap., 2017,
vol. 71, p. 949.
https://doi.org/10.1007/s11696-016-0018-2
8. Tartter, A. and Hausmann, H., FRG Patent Appl.
no. 812312, 1951.
9. Burdick, D.L. and Osborn, M.D., US Patent no. 3230220,
1966.
10. Rasberger, M. and Karrer, F., US Patent no. 4317911,
1982.
N1,N2-Bis(2-hydrazinyl-2-oxoethyl)hydrazine-
1,2-dicarboxamide (12) (general proedure). A suspen-
sion of 0.013 mol of compound 2a, 2b, or 4 in 50 mL
of 30% aqueous hydrazine was stirred at room tempera-
ture for 48 h. The precipitate was filtered off, washed
with water and acetone, and dried in air. Yield 35%, 47,
or 32% from 2a, 2b, or 4, respectively; white powder,
1
mp 201–202°C (decomp.). H NMR spectrum
(DMSO-d6), δ, ppm: 3.62 d (2H, CH2, J = 4.0 Hz),
4.20 s (2H, NH2), 6.83 br.s (1H, NH), 7.86 s (1H, NH),
8.88 s (1H, NH). 13C NMR spectrum (DMSO-d6), δC,
ppm: 42.15 (CH2), 159.04 (CO), 169.37 (CO). Mass
spectrum: m/z 263 (Irel 100%) [M + H]+. Found, %:
C 27.28; H 5.68; N 42.55. C6H14N8O4. Calculated, %:
C 27.48; H 5.38; N 42.73. M 262.23.
11. Illy, H. and Fussenegger, W., US Patent no. 4127718,
1978.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 6 2020