Russ. Chem. Bull., Int. Ed., Vol. 70, No. 1, January, 2021
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2,4,6,8-Tetramethylol-2,4,6,8-tetraazabicyclo[3.3.0]octane-
3,7-dione (1). 1H NMR (D2O), δ: 5.59 (s, 2 H, CHCH); 4.75
(d, 4 H, CH2OH, J = 11.1 Hz); 4.66 (d, 4 H, CH2OH,
J = 11.1 Hz). 1H NMR (DMSO-d6), δ: 5.94 (s, 4 H, OH); 5.47
(s, 2 H, CHCH); 4.76 (d, 4 H, CH2OH, J = 11.0 Hz); 4.66 (d,
4 H, CH2OH, J = 11.0 Hz). 13C NMR (D2O), δ: 158.62 (C=O),
70.65 (CH), 66.29 (CH2). 13C NMR (DMSO-d6), δ: 157.55
(C=O), 70.65 (CH), 66.32 (CH2). HMBS 1H—15N (DMSO-d6),
δ: 112.57 (N—CH2OH).
the attainment of local minima on the potential energy surface.
The conformations of compounds 2—6 were modeled on the
basis of the found most stable conformers of molecule 1 remov-
ing the corresponding number of the hydroxymethyl groups and
optimizing the geometry by the DFT method as described above.
Results and Discussions
Compound 1 is a white powder, soluble in water and
DMF and poorly soluble in most organic solvents. Com-
pound 1 was synthesized according to the published
procedures7,17 by condensation of formaldehyde with
glycoluril under basic catalysis (Scheme 2).
2,4,6-Trimethylol-2,4,6,8-tetraazabicyclo[3.3.0]ocatne-3,7-
1
dione (2). H NMR (D2O), δ: 7.70 (s, 1 H, NH); 5.62 (d, 1 H,
CHCH, J = 8.5 Hz); 5.51 (d, 1 H, CHCH, J = 8.5 Hz); 4.85,
4.38 (both d, 1 H each, CH2OH, J = 10.8 Hz); 4.78, 4.71 (both d,
1 H each, CH2OH, J = 10.9 Hz); 4.61, 4.49 (both d, 1 H each,
1
CH2OH, J = 11.0 Hz). H NMR (DMSO-d6), δ: 7.83 (s, 1 H,
NH); 6.31 (s, 1 H, OH); 5.75 (s, 2 H, OH); 5.47 (d, 1 H, CHCH,
J = 8.5 Hz); 5.33 (d, 1 H, CHCH, J = 8.5 Hz); 4.86, 4.37 (both d,
1 H each, CH2OH, J = 10.8 Hz); 4.79, 4.72 (both d, 1 H each,
CH2OH, J = 10.9 Hz); 4.61, 4.50 (both d, 1 H each, CH2OH,
J = 11.0 Hz).13C NMR (D2O), δ: 160.82 (C=O), 158.30 (C=O),
67.73 (CH2), 66.32 (CH2), 65.86 (CH), 64.78 (CH), 62.44
(CH2). 13C NMR (DMSO-d6), δ: 159.30 (C=O), 157.12 (C=O),
67.73 (CH2), 66.22 (CH2), 65.88 (CH), 64.79 (CH), 62.44
(CH2). HMBS 1H—15N (DMSO-d6), δ: 90.76 (NH), 112.57
(N—CH2OH).
Scheme 2
2,4-Dimethylol-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-
dione (3). 1H NMR (D2O), δ: 7.47 (s, 2 H, NH); 5.55 (s, 2 H,
CHCH); 4.35—4.90 (m, 4 H, CH2OH). 13C NMR (D2O), δ:
163.47 (C=O), 158.01 (C=O), 64.10—67.70 (CH, CH2).
2,6-Dimethylol-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-
dione (4). 1H NMR (D2O), δ: 7.61 (s, 2 H, NH); 5.53 (s, 2 H,
CHCH); 4.35—4.90 (m, 4 H, CH2OH). 13C NMR (D2O), δ:
160.56 (C=O), 64.10—67.70 (CH, CH2).
A freshly prepared sample of compound 1 was analyzed
by 1H, 13C, and 1H—15N NMR spectroscopy in DMSO-d6
to minimize hydrolysis. We found that the NMR spectrum
of the sample contains signals of compounds 1 and
its dehydroxymethylated product, tris(hydroxymethyl)-
glycoluril (2), that is present in an amount of ∼14% (cal-
culated from the integrated intensity of the 1H NMR
signals). In particular, the chemical shift at δH 7.83 is at-
tributable to the proton signal of the unsubstituted amino
group of compound 2 (Fig. 1). The signals at δH 5.75 and
6.31 are assigned to the OH group protons of tris-
(hydroxymethyl)glycoluril 2. The doublets at δH 5.33 and
5.47 are ascribed to methine CH protons that are the
magnetically inequivalent since the trisubstituted structure
2 is antisymmetric.
2,8-Dimethylol-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-
1
dione (5). H NMR (D2O), δ: 7.39 (s, 2 H, NH); 5.58 (d, 1 H,
CHCH, J = 8.4 Hz); 5.42 (d, 1 H, CHCH, J = 8.4 Hz); 4.35—4.90
(m, 4 H, CH2OH). 13C NMR (D2O), δ: 160.90 (C=O); 64.10—67.70
(CH, CH2).
2-Methylol-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione
1
(6). H NMR (D2O), δ: 7.29 (s, 1 H, NH); 7.22 (s, 1 H, NH);
7.17 (s, 1 H, NH); 5.65 (d, 1 H, CHCH, J = 8.4 Hz); 5.45 (d, 1 H,
CHCH, J = 8.4 Hz); 4.35—4.90 (m, 2 H, CH2OH). 13C NMR
(D2O), δ: 160.08 (C=O), 158.30 (C=O), 64.10—67.70 (CH, CH2).
High performance liquid chromatography was carried out on
a liquid chromatograph Agilent 1260 Infiniti using a PerfectSil
Target ODS-3 HD column (5 μm, 250×4.6 mm) from MZ-Anal-
ysentechnik (Germany), the column temperature was set at 40 °C
and a flow rate was 1.5 mL min−1. An overall analytical run time
was 10 min. Water was used as a mobile phase. The probe volume
was 10 μL. The samples were prepared by dissolving a weighed
portion of compound 1 (100 mg) in water (10 mL).
1
In the H—15N HMBS NMR spectrum, in addition
to the intense cross-peaks of the 15N nucleus (δN 112.57)
with the CH (δH 5.47) and CH2 protons (δH 4.76) of
compound 1, a cross-peak of the nitrogen nucleus
(δN 90.76) with the CH proton (δH 5.33) of tris(hydroxy-
methyl)glycoluril 2 was observed (Fig. 2).
The HPLC analyses were carried out using freshly
prepared aqueous solution of compound 1. To prevent
hydrolysis, compound 1 was dissolved in a formaldehyde—
water mixture (1 : 9, weight ratio) and the chromatogram
of sample I was obtained (Table 1).
A systematic conformational search for compound 1 was
performed using the Conformational Search module imple-
mented in the HyperChem 7 software package (Hypercube, USA)
by varying all torsion angles around the exocyclic N—C and C—O
bonds with optimization of the geometry of conformers by the
semi-empirical method PM3.13 The obtained set of independent
conformers was further optimized in the gas phase by the DFT
method with the B3LYP functional14,15 and the 6-311+G (2d,p)
basis set16 using Gaussian 16 program. The absence of imaginary
values in the wave numbers for all the structures studied confirmed
The data obtained (see Figs 1 and 2 and Table 1) in-
dicated that compound 1 immediately after dissolution
underwent monodehydroxymethylation to give compound 2