Synthesis of Novel Phosphorus-Containing Derivatives of 1,3,4-Trimethylglycoluril via the Birum–Oleksyszyn Reaction

Abstract

This work presents the synthesis of a new compound, 1-[aryl-(diphenylphosphono)methyl]-3,4,6-trimethylglycolurils, via the interaction of benzaldehyde and its mononitro- and monohydroxyderivatives with 1,3,4-trimethylglycoluril and triphenylphosphite. By varying the reaction conditions and the catalysts, the obtained product yields ranged from satisfactory to good. The diastereomers formed during the reaction were separated by semipreparative HPLC on the C18 stationary phase. The isolated diastereomers were characterized by ¹H, ¹³C, and ³¹P NMR, and the structures of the diastereomers were confirmed using a single-crystal X-ray crystal structure analysis and quantum chemical calculations.

1. Introduction

Glycoluril derivatives have attracted the attention of researchers due to their wide range of applications and, above all, due to their biological activities, particularly their nootropic, neurotropic, anxiolytic [1,2], and antibacterial properties [3,4]. Additionally, glycoluril derivatives are widely used as “building blocks” to synthesize supramolecular compounds such as bambus[n]urils [5,6], cucurbit[n]urils [7,8], and molecular clips [9,10]. Special attention has been paid to studying methods for synthesizing new glycoluril derivatives and their structural analogs and precursors as well as to the characterization of their properties [11,12,13,14,15]. Individual phosphorus-containing glycoluril derivatives are described in the literature [16,17], where their catalytic activity in some three-component reactions has been shown. Phosphorylated glycoluril derivatives were investigated as flame-resistant additives for rubber [18] and as moleculars tweezer exhibiting high binding properties to aliphatic amines [19]. However, these reports are sporadic, and to date, only a relatively small number of synthetic approaches have been developed for preparing phosphorus-containing glycoluril derivatives [16,17,18,19], and the main regularities of the formation of stereoisomers of the phosphonate derivatives of glycoluril have not been established either. We previously found [20] that the interaction of 1,3,4-trimethylglycoluril with aliphatic aldehydes and triphenylphosphite in acetonitrile using methanesulfonic acid as a catalyst led to the formation of 1-[1-(diphenylphosphono)alkyl]-3,4,6-trimethylglycoluril.

2. Results and Discussion

2.1. The Effect of Synthesis Conditions on the Yield of Phosphonate Derivatives of 1,3,4-Trimethylglycoluriles

In order to extend the methods for synthesizing phosphorus-containing glycoluril derivatives, we studied the conditions for the synthesis of various new glycoluril phosphonates 4a–f using the Birum–Oleksyszyn approach exemplified by 1,3,4-trimethylglycoluril and benzaldehydes 2a–2f (Scheme 1).

It is noteworthy that the attempt to synthesize phosphonate derivatives of 1,3,4-trimethylglycoluryl 4a was unsuccessful under typical conditions used to prepare diphenyl 1-aminophosphonates [21], namely, with glacial acetic acid as a solvent. Thus, according to the NMR analysis of the reaction mixture, the triphenylphosphite 3 interaction with benzaldehyde 2a in glacial acetic acid with 1,3,4-trimethylglycoluril 1 (80 °C, 2 h) led to the formation of target compound 4a with a low yield of 21%. In addition, the ³¹P NMR spectra of the reaction mixture contained clear signals within 3.40–−0.57 ppm, indicating both partial and complete hydrolysis of the ester groups for compound 3 as well as the formation of α-hydroxyphosphonate 6a (³¹P δ = 15.99 ppm) as a by-product (Scheme 2) (Supplementary Materials, Figure S1).

The authors carried out the selection of catalysts, solvents, temperatures, and reaction times to establish the optimal conditions for synthesizing the target product 4a because the typical conditions for the synthesis of α-aminophosphonates proved to be inefficient in obtaining phosphonate derivatives of 1,3,4-trimethylglycoluryl 1.

A series of model syntheses of compound 4a was carried out to select the optimal reaction conditions considering the fact that Lewis acids and organic Brønsted acids tend to show a catalytic effect in the Birum–Oleksyszyn reaction [22,23]. Therefore, the reaction was carried out in anhydrous acetonitrile; AlCl₃, BF₃·Et₂O, SnCl₄, and TiCl₄ were used as Lewis acids, whereas trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid were used as Brønsted acids in addition to glacial acetic acid (

Table 1. The effect of a catalyst on the maximum analytical yield of 4a in the reaction mixture at room temperature in acetonitrile.

No.	Catalyst	pKa	Reaction Time, min	Yield, % (Analytical)
1	CH3COOH	4.75	360	5
2			580	10
3	CF3COOH	0.23	580	58
4	CH3SO3H	−1.90	30	91 (82) 1
5	CF3SO3H	−14.70	30	38 1
6			30	75 1,2
7	BF3 Et2O		180	25
8	TiCl4		30	24
9	AlCl3		30	15
10	CH3COOH	solvent	60	23 3

¹ Isolated yield. ² With the addition of Ac₂O as a dehydrating agent. ³ CH₃COOH as a solvent.

). The amount of catalyst equaled 10 mol% of the total mass of the reaction mixture, and the process was carried out at room temperature. The reaction flow was monitored by HPLC.

Table 1 shows that the use of glacial acetic acid as a solvent resulted in a relatively low yield of the target product 4a (23%). The maximum concentration of the latter in the reaction mixture was reached within 60 min according to HPLC (Table 1, entry 10). However, with glacial acetic acid as a catalyst and acetonitrile as a solvent, the content of 4a remained relatively low, although it increased with time (Table 1, entries 1 and 2).

If trifluoroacetic, methanesulfonic, and trifluoromethanesulfonic acids (i.e., organic acids stronger than acetic acid) are applied as catalysts, the content of the target product 4a in the reaction mixture increases by up to nine times (Table 1, entries 3, 4, and 5). When trifluoroacetic acid is applied within a comparable reaction time, the analytical yield of 4a becomes almost six times higher than in the case of synthesis with glacial acetic acid.

For methanesulfonic acid, the maximum yield for trimethylphosphonate glycoluril 4a equaled 91% (82% isolated preparatively). This yield was achieved within 30 min under the selected reaction conditions. An increase in the reaction time when using methanesulfonic acid led to a decrease in the concentration of the target product 4a, which might indicate hydrolysis and the formation of the reaction by-products.

The application of trifluoromethanesulfonic acid also leads to a notable increase in the content of the target substance 4a for a relatively short reaction time (Table 1, entry 5), but the analytical yield of compound 4a is only 38%. We assume that trifluoromethanesulfonic acid not only promotes the main reaction but also catalyzes the side reactions, namely, the hydrolysis of the initial triphenylphosphite 3 and of the target compound 4a. Furthermore, trifluoromethanesulfonic acid might promote the formation of α-hydroxyphosphonate 6a (Scheme 2). To verify this assumption, we conducted an additional experiment and added acetic anhydride to the reaction mixture with trifluoromethanesulfonic acid as a catalyst in order to chemically bind the water formed during the reaction. Thus, we established that the practical yield of the target compound 4a sharply increased by up to 75% for a comparable reaction time, which implicitly confirms the assumption (Table 1, entry 6).

If Lewis acids (AlCl₃, BF₃·Et₂O, SnCl₄ and TiCl₄) are applied as catalysts in the model reaction to prepare compound 4a (Table 1, entries 7–9), the yields of the target compound reach 15–25%.

In the course of the further selection of the conditions to prepare compound 4a, we studied the effect of solvents on the target product yield under the same conditions (room temperature, methanesulfonic acid as a catalyst, 10 mol%).

Table 2. The effect of a solvent on the maximum analytical yield of the target product 4a (methanesulfonic acid as catalyst (10 mol%), room temperature).

No.	Solvent	ε (Permittivity)	Time, min	Yield, % (Analytical)
1	1,4-Dioxane	2.21	180	55
2	Benzene	2.27	120	29
3	Chloroform	4.81	120	59
4	Acetonitrile	38.00	30	91
5	Methanol	32.63	60	8
6	DMSO	45.00	180	0

shows the results obtained.

Despite a rather low solubility of the initial 1,3,4-trimethylglycoluril 1 in nonpolar solvents at room temperature, the analytical yield of the phosphonate glycoluril 4a is relatively high and varies from 29 to 59% (Table 2, entries 1–3). At the same time, the maximum analytical yield of 91% (82% being a preparative yield) is achieved in an aprotic medium polar solvent, i.e., acetonitrile. The use of a more polar aprotic solvent, DMSO, does not lead to the formation of the product 4a in notable amounts according to HPLC. If methanol is applied as a reaction solvent, the highest analytical yield is achieved in 60 min and amounts to only 8%.

It has been experimentally established that an increase in the reaction temperature within 40 to 70 °C—with acetonitrile as a solvent and methanesulfonic acid as a catalyst—led to a decrease in the yield of compound 4a. Thus, at 40 °C, the maximum analytical yield of product 4a was 64% for 20 min. At 70 °C, the maximum analytical yield of 4a equaled 50% for 20 min.

In sum, the optimal conditions for the three-component Birum–Oleksyszyn reaction in the case of 1,3,4-trimethylglycoluril 1 (Scheme 1) appear to be the use of acetonitrile as a solvent (room temperature) and the use of methanesulfonic acid as a catalyst (10 mol% of the total reaction mixture). A decrease in the amount of catalyst to 5 mol% or its increase to 20 mol% results in decreases in the yield of the desired product 4a to 62% and 54%, respectively.

2.2. Separation and Identification of Diastereomers of Phosphonate Derivatives of 1,3,4-Trimethylglycoluriles 4a′ and 4a″

The individual diastereomers 4a′ and 4a″ were preparatively separated and isolated by HPLC with a C18 stationary phase. The diastereomers were then characterized by NMR and single-crystal X-ray diffraction analysis (SCXRD). Obviously, the order of elution for diastereomers 4a′ and 4a″ depends on the mutual arrangement of the substituents around the asymmetric C7 centers (Scheme 1). The highest retention is characterized by the 4a″ isomer with the most sterically accessible hydrophobic groups.

2.2.1. X-ray Crystal Structure Analysis of the Diastereomers 4a′ and 4a″

Compound 4a′ crystallizes in a monoclinic crystal system, space group C2/c. The asymmetric unit contains one 4a′ molecule and one and a half acetonitrile solvate molecules (Figure 1a). The unit cell contains eight formula units. The crystallographic space group is centrosymmetric; therefore, both enantiomeric forms of compound 4a′ crystallize as a true racemate. The configuration of the stereocenters (3a, 6a, CHPO₃) in compound 4a′ is as follows: R,S,R (and enantiomeric S,R,S) (Figure 1).

The molecules of 4a′ of the same enantiomeric form are joined into homochiral supramolecular chains by short CH···O contacts involving the oxygen atoms of the phosphonate group and the hydrogen atoms of the phenyl (d(O3–H22) = 2.60 Å) or glycoluril fragments (d(O2–H10) = 2.48 Å, Figure 2a). The second type of CH···O contacts involves the carbonyl oxygen atom and aliphatic hydrogen atoms with the distances d(O4–H7) = 2.43 Å and d(O4–H10) = 2.40 Å, respectively. The chains are oriented along the crystallographic axis b. The enantiomeric chains of opposite stereochemistry are joined in the crystal packing by π-π stacking interactions between the phenyl groups of the phosphonate ester moiety with the distance of 3.295 Å between the planes of the rings (Figure 2b).

Compound 4a″ crystallizes in a monoclinic centrosymmetric space group, P2₁/c. In contrast to compound 4a′, there are no solvate molecules in the crystal structure, and the asymmetric unit consists of one molecule (Figure 1b). The unit cell contains four formula units. Similarly to compound 4a′, the enantiomeric pair of 4a″ crystallizes as a true racemate. The configuration of the stereocenters (3a, 6a, CHPO₃) is S,R,R (and R,S,S). Therefore, compounds 4a′ and 4a″ differ in the absolute configuration of the carbon atom connected to the phosphonate group, in accordance with the two possible directions of the 1,3,4-trimethylglycoluril addition to the carbonyl group of the aldehyde.

Similarly to compound 4a′, the enantiomers of 4a″ of the same configuration are joined into supramolecular chains oriented along the crystallographic axis b (Figure 3a), but the short CH···O contacts of the phosphonate groups involve only the hydrogen atoms of the phenyl rings (d(O2–H6) = 2.53 Å and d(O3–H15) = 2.65 Å). The carbonyl oxygen atoms form only one type of short CH···O contacts with the hydrogen atoms of the glycoluril fragment (d(O4–H9) = 2.65 Å). In the crystal packing, the enantiomers of 4a″ are joined only by C–H···π (d(C19–H25C) = 2.76 Å) contacts, and no other specific supramolecular interactions were found.

2.2.2. Stereoisomerization of Nitro- and Hydroxyphosphonate Derivatives of 1,3,4-Trimethylglycoluriles 4b–f

Further studies were focused on establishing the stereochemical features of obtaining phosphonate derivatives of 1,3,4-trimethylglycoluryl 4b–f with the participation of nitro- and hydroxy derivatives of benzaldehyde 2b–f (Scheme 1) using HPLC, NMR spectroscopy, and quantum chemical calculations.

The reactions of nitro- 2b, 2d, and 2f and hydroxybenzaldehydes 2c and 2e with 1,3,4-trimethylglycoluril 1 and triphenylphosphite 3 under the selected conditions (acetonitrile and 10 mol% methanesulfonic acid) proceeded with satisfactory yields of 4b–4f (36–67%). According to HPLC, the compounds with structures 4a″, 4b″, 4c″, 4d″, and 4e″ were formed in a diastereomeric excess (Scheme 1). For compound 4f″, the diastereomeric excess equaled 96%.

The X-ray crystal structures and NMR results for diastereomers 4a′ and 4a″ were compared with the NMR spectroscopy data for compounds 4b–f. Thus, for diastereomer 4′, the signals of the methine protons of ¹H CH-CH bond were recorded by two doublets within a narrow region of 5.11–5.37 ppm, while for compound 4″, the signals of these protons were recorded within a broader region of 4.95–5.51 ppm. The ³¹P spectra for the type 4′ diastereomers are characterized by a signal shift towards the weak field relative to the signal of the type 4″ compounds. The nature of the substituent in the meta- and para-position does not significantly affect the final ratio of the diastereomers of products 4b–e. However, we observed a notable decrease in the yield of reaction products with a para-substituent (the yields for 4d and 4e are 40% and 36%, respectively) compared to the reaction products with a meta-substituent (yields of 4b and 4c are 60% and 67%, respectively). In the case of compound 4f, only one diastereomer was isolated from the reaction mixture and assigned to the 4f″ structure. According to HPLC-MS, the application of 2-hydroxybenzaldehyde under the conditions of interest did not allow for the detection of any hydrolysis products of compound 4f′ or any ions with the mass that could be assigned to this compound.

Comparing the positions of diastereomeric structures for the phosphonates of 1,3,4-trimethylglycoluriles (4a–f) on the energy profile (Table S1 Supplementary Materials) indicates a larger thermodynamic stability of the 4″-type structures regardless of the nature and position of the substituent in the aromatic ring. This correlates with the experimental data on the ratio of 4′:4″ stereoisomers (Scheme 1). The changes in the electron energy and enthalpy of the isomeric transition of 4″-type structures to 4′-type structures range from 2.85 to 3.58 kcal/mol and from 2.92 to 3.93 kcal/mol, respectively (Table S2 Supplementary Materials).

2.2.3. The Diastereomers of the Phosphonate Derivatives of 1,3,4-Trimethylglycolyrils (4a–f): General Regularities in the NMR Spectra

NMR spectroscopy was applied to reliably identify the diastereomers of phosphonate derivatives of 1,3,4-trimethylglycolyrils 4a–f.

Table 3. The comparison of experimental and pre-calculated chemical shifts for hydrogen atoms of the 3a, 6a, and CHPO₃ carbon atom of the compounds 4a–f.

Structure	δ 1H of CHPO3 Proton, ppm	δ 1H of 6a Proton, ppm	δ 1H of 3a Proton, ppm	δ 13C of CHPO3, ppm	δ 13C of 6a, ppm	δ 13C of 3a, ppm	δ 31P, ppm
4a′ (RSR/SRS) calc	5.33	5.26	5.25	56.34	70.64	70.27	10.28
4a′ (RSR/SRS) exp	5.77	5.28	5.24	57.37	72.40	72.14	14.06
4a″ (SRR/RSS) calc	6.57	5.2	2.74	48.77	67.85	68.08	8.00
4a″ (SRR/RSS) exp	5.85	5.5	5.0	53.84	70.38	72.32	13.35
4b′ (RSR/SRS) calc	5.49	5.28	5.35	56.02	70.22	70.01	6.79
4b′ (RSR/SRS) exp	5.97	5.37	5.26	57.44	72.69	72.41	12.77
4b″ (SRR/RSS) calc	6.57	5.24	3.11	48.35	67.13	68.45	3.88
4b″ (SRR/RSS) exp	5.97	5.49	5.08	54.02	71.00	72.46	12.32
4c′ (RSR/SRS) calc	5.28	5.27	5.24	56.22	70.54	70.18	10.22
4c′ (RSR/SRS) exp	5.64	5.15	5.15	54.92	70.30	69.79	14.16
4c″ (SRR/RSS) calc	6.48	5.22	2.81	48.54	67.76	68.14	7.02
4c″ (SRR/RSS) exp	5.76	5.49	4.97	51.47	68.62	70.16	13.35
4d′ (RSR/SRS) calc	5.43	5.27	5.29	55.55	70.20	70.07	8.36
4d′ (RSR/SRS) exp	5.98	5.36	5.25	57.88	72.77	72.26	11.29
4d″ (SRR/RSS) calc	6.53	5.16	3.12	48.59	67.34	68.19	3.96
4d″ (SRR/RSS) exp	5.98	5.51	5.1	50.53	68.62	70.31	10.48
4e′ (RSR/SRS) calc	5.22	5.22	5.23	55.67	70.53	70.15	10.25
4e′ (RSR/SRS) exp	5.64	5.11	5.11	54.34	70.40	69.61	14.56
4e″ (SRR/RSS) calc	6.48	5.17	2.72	48.17	67.82	68.05	8.48
4e″ (SRR/RSS) exp	5.71	5.48	4.95	53.36	70.64	72.27	13.87
4f′ (RSR/SRS) calc	6.66	5.44	5.37	49.55	69.62	70.10	5.99
4f′ (RSR/SRS) exp	-	-	-	-	-	-	-
4f″ (SRR/RSS) calc	6.69	4.85	3.62	47.34	66.85	70.46	6.31
4f″ (SRR/RSS) exp	6.35	5.49	5.11	50.04	72.48	70.83	11.67

presents the results of comparing the experimental and pre-calculated values for the chemical shifts of the hydrogen atoms in bridging the methine groups of the glycoluril fragment (3a and 6a) and the hydrogen atom bonded to the carbon atom in the CHPO₃ group. The correlations between the experimental and pre-calculated δ values for all of these atoms can be found in Supplementary Materials (Figure S52).

Table 3 shows that the δ for the hydrogen atom bonded to the carbon atom in the CHPO₃ group, as well as the methine protons of the bridging CH-CH (3a, 6a) group, can indicate the configuration of the phosphonate substituent in structure 4. Thus, the signals of the protons in the carbon atom with a phosphonate substituent (CHPO₃) of type 4′ (RSR, SRS) are shifted towards lower values compared to the signals of the enantiomers of type 4″ (SRR, RSS). For example, the experimental and pre-calculated chemical shifts equal 5.77 and 5.33 ppm, respectively, for the hydrogen atoms bonded to the carbon atom of the phosphonate group (CHPO₃) in the RSR and SRS enantiomers of compound 4a′. However, these shifts equal 5.85 and 6.57 ppm, respectively, for the hydrogen atoms of the SRR and RSS enantiomers of compound 4a″. This pattern persists for the unsubstituted and OH-substituted synthesized glycoluril phosphonates 4a, 4c, and 4e. The experimental signals for similar hydrogen atoms in the indicated pairs of diastereomers of the nitro derivatives (4b, 4d, and 4f) have identical chemical shifts, while the pre-calculated chemical shifts sustain the trend. At the same time, for δ ³¹P, we observed a significant discrepancy between the pre-calculated values and the experimental ones. This latter fact might be related to the calculation methodology.

A comparison of the experimental and pre-calculated δ values for the hydrogen atoms bonded to the carbon atom in the phosphonate substituent (CHPO₃) and for the bridging CH-CH (3a, 6a) group demonstrates the significant discrepancy in these values for the enantiomeric pairs of the SRR and RSS (4″) types and indicates the values’ precision for the RSR and SRS (4′) pairs. For example, the experimental δ of the carbon proton (CHPO₃) and CH-CH protons (3a, 6a) in the compound of group 4a″ equal 5.85, 5.50, and 5.00 ppm, whereas the pre-calculated ones equal 6.57, 5.20, and 2.74 ppm. This discrepancy might be caused by the fact that the most stable pre-calculated conformations of structure 4a″ (SRR and RSS) contain the phenyl rings located relative to the glycoluril fragment, thus creating anisotropy cones and shielding the farthest methine proton in the bridging group (CH-CH). At the same time, the hydrogen atom in the methine group of the phosphonate substituent remains in the de-shielding region (Figure 4). This effect is not observed in the experimental ¹H NMR spectra, which might be linked to the impossibility of tracking the solvating effect of the solvent using ab initio methods and to the respective change in the structure conformations in the actual solution. The observed effect of phenyl rings on the SRR- and RSS-type enantiomers is retained for the OH and NO₂ derivatives (4b″–4f″).

The 2D correlation experiment (NOESY) was performed for compounds 4a′ and 4a″. The interactions between the protons of the 3a, 6a, and CHPO₃ sites were identified for compound 4a′, while these interactions were not detected for compound 4a″ (Supplementary Materials, Figures S35 and S36).

3. Materials and Methods

All reagents (Acros Organics, Merck, Rahway, NJ, USA) were used as purchased, unless indicated otherwise. Solvents for HPLC (PanReac AppliChem, Darmstadt, Germany) were used for the reactions, benzene was dried over molecular sieves 3A for 48 h. 1,3,4-trimethylglycoluril was prepared according to a known procedure [24] and used as a racemate. ¹H NMR (400 MHz, Chloroform-d): δ 7.46 (s, 1H), 5.12 (dd, J = 1.7, 8.3 Hz, 1H), 4.97 (d, J = 8.3 Hz, 1H), 2.92 (s, 3H), 2.88 (s, 3H), 2.77 (d, J = 1.6 Hz, 3H). ¹³C NMR (101 MHz, Chloroform-d) δ 160.61, 158.41, 73.83, 65.94, 30.47, 29.55, 27.96.

3.1. General Procedure for the Synthesis of Compounds 4a–4f

Aldehyde 2 (2 mmol), triphenyl phosphite 3 (2 mmol), and methanesulfonic acid (10 mol%) were added to the suspension of 1,3,4-trimethylglycoluril 1 (2 mmol) in dry acetonitrile (4 mL) in an argon atmosphere. The mixture was stirred for 1 h at room temperature and then distilled on a rotary evaporator. The residue was dissolved in 10 mL of toluene and washed with 5% aqueous Na₂CO₃ solution (3 × 10 mL). The toluene solution was then washed with water (3 × 10 mL). Upon washing, the organic layer was dried over Na₂SO₄ and concentrated on a rotary evaporator. Concentrated viscous oil was purified by preparative HPLC with C18 stationary phase and water–acetonitrile (60:40) mobile phase.

3.2. NMR Spectroscopy

¹H, ¹³C, and ³¹P NMR spectra were recorded using the Bruker AVANCE III HD 400 MHz NMR spectrometer (Brucker BioSpin GmbH, Ettlingen, Germany) with the PA BBO 400S1 BBF-H-D-05 Z SP probe head and the BCU temperature control unit, PLC on TTY1 of ELCB 1 autosampler, and TopSpin 3.5 pl5 interface. The ¹H and ¹³C NMR signals of the samples were assigned to the ¹H and ¹³C NMR signals of tetramethylsilane (TMS) (0.0 ppm), and the ³¹P NMR signals were assigned to the ³¹P NMR signals of H₃PO₄ (0.0 ppm). Figures S2–S34 (Supplementary Materials) show the ¹H, ¹³C, and ³¹P NMR spectra of the compounds.

Diphenyl ((1S)-phenyl(3,4,6-trimethyl-2,5-dioxohexahydroimidazo[4,5-d]imidazol-1(2H)-yl)methyl)phosphonate (4a′), white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 7.75–7.70 (m, 2H), 7.54–7.45 (m, 4H), 7.42–7.33 (m, 4H), 7.28–7.19 (m, 2H), 7.12–7.05 (m, 2H), 6.97 (dt, J = 8.5, 1.2 Hz, 2H), 5.77 (d, J = 27.4 Hz, 1H), 5.28 (dd, J = 8.5, 1.3 Hz, 1H), 5.24 (d, J = 8.5 Hz, 1H), 2.94 (s, 3H), 2.88 (s, 3H), 2.57 (s, 3H). ¹³C NMR (101 MHz, DMSO): 159.06, 158.37 (d, J = 3.7 Hz), 150.59 (d, J = 9.9 Hz), 134.76, 130.17 (d, J = 18.7 Hz), 129.45 (d, J = 6.6 Hz), 129.12, 125.55 (d, J = 15.0 Hz), 120.90 (dd, J = 9.1, 4.1 Hz), 72.40, 72.14 (d, J = 5.0 Hz), 57.37 (d, J = 155.9 Hz), 30.70, 30.27, 30.13; ³¹P NMR (162 MHz, DMSO-d6): δ 14.06 (d, J = 27.1 Hz). MS (HRMS-ESI): Calcd. For C₂₆H₂₇N₄O₅P, [M + H]⁺: 507.1792, found: m/z 507.1823.

Diphenyl ((1R)-phenyl(3,4,6-trimethyl-2,5-dioxohexahydroimidazo[4,5-d]imidazol-1(2H)-yl)methyl)phosphonate (4a″) white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 7.65 (d, J = 7.5 Hz, 2H), 7.50–7.35 (m, 8H), 7.30–7.21 (m, 2H), 7.17 (d, J = 8.1 Hz, 2H), 7.13–7.07 (m, 2H), 5.85 (d, J = 25.8 Hz, 1H), 5.50 (d, J = 8.5 Hz, 1H), 5.00 (d, J = 8.5 Hz, 1H), 2.88 (s, 3H), 2.82 (s, 3H), 2.16 (s, 3H). ¹³C NMR (101 MHz, DMSO): δ 159.41, 158.11 (d, J = 2.9 Hz), 150.02 (dd, J = 9.7, 3.3 Hz), 130.57 (d, J = 7.9 Hz), 129.28, 129.03, 129.00, 128.95, 126.15, 120.73 (dd, J = 20.8, 4.1 Hz), 72.32, 70.78, 53.84 (d, J = 155.3 Hz), 30.85, 30.75, 30.26; ³¹P NMR (162 MHz, DMSO-d₆): δ 13.35 (d, J = 25.9 Hz). MS (HRMS-ESI): Calcd. for C₂₆H₂₇N₄O₅P, [M + H]⁺: 507.1792, found: m/z 507.1825.

Diphenyl ((1S)-(3-nitrophenyl)(3,4,6-trimethyl-2,5-dioxohexahydroimidazo[4,5-d]imidazol-1(2H)-yl)methyl)phosphonate (4b′) yellow viscous oil. ¹H NMR (400 MHz, DMSO-d₆): δ 8.57 (s, 1H), 8.28–8.24 (m, 1H), 8.08 (d, J = 5.7 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.46–7.33 (m, 4H), 7.32–7.24 (m, 2H), 7.24–7.16 (m, 2H), 7.14–7.07 (m, 2H), 5.98 (d, J = 27.4 Hz, 1H), 5.36 (d, J = 8.4 Hz, 1H), 5.25 (d, J = 8.5 Hz, 1H), 2.89 (s, 3H), 2.85 (s, 3H), 2.49 (s, 3H). ¹³C NMR (101 MHz, DMSO-d₆): δ 158.79, 158.42 (d, J = 3.1 Hz), 150.59 (d, J = 10.2 Hz), 150.45 (d, J = 10.0 Hz), 148.22, 137.96 (d, J = 2.3 Hz), 135.77 (d, J = 5.9 Hz), 130.72, 130.39, 130.08, 125.79, 125.50, 124.10, 124.04, 123.72, 120.82, 120.78, 120.72, 120.68, 72.69 (d, J = 4.9 Hz), 72.41, 57.44 (d, J = 152.4 Hz), 30.75, 30.16, 29.86. ³¹P NMR (162 MHz, DMSO-d₆): δ 12.77 (d, J = 27.8 Hz); MS (HRMS-ESI): Calcd. for C₂₆H₂₆N₅O₇P, [M + H]⁺: 552.1643, found: m/z 552.1641.

Diphenyl ((1R)-(3-nitrophenyl)(3,4,6-trimethyl-2,5-dioxohexahydroimidazo[4,5-d]imidazol-1(2H)-yl)methyl)phosphonate (4b″) yellow viscous oil. 1H NMR (400 MHz, DMSO-d₆): δ 8.57 (s, 1H), 8.28 (dd, J = 2.3, 8.1 Hz, 1H), 8.10 (d, J = 7.7 Hz, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.45–7.36 (m, 5H), 7.31–7.24 (m, 2H), 7.20–7.16 (m, 2H), 7.13–7.09 (m, 2H), 5.98 (d, J = 27.0 Hz, 1H), 5.51 (d, J = 8.5 Hz, 1H), 5.10 (d, J = 8.5 Hz, 1H), 2.90 (s, 3H), 2.85 (s, 3H), 2.40 (s, 3H).¹³C NMR (101 MHz, DMSO-d₆): δ 159.47, 157.94 (d, J = 2.9 Hz), 150.00 (d, J = 5.5 Hz), 149.90 (d, J = 5.4 Hz), 148.17, 136.84 (d, J = 6.4 Hz), 135.68 (d, J = 7.9 Hz), 130.89, 130.65, 130.52, 126.30, 126.18, 123.95, 123.71, 123.63, 120.83, 120.78, 120.72, 120.68, 72.46, 71.00, 54.02 (d, J = 157.3 Hz), 31.08, 30.86, 30.29. ³¹P NMR (162 MHz, DMSO-d₆): δ 12.32 (d, J = 26.8 Hz); MS (HRMS-ESI): Calcd. for C₂₆H₂₆N₅O₇P, [M + H]⁺: 552.1643, found: m/z 552.1646.

Diphenyl ((1S)-(3-hydroxyphenyl)(3,4,6-trimethyl-2,5-dioxohexahydroimidazo[4,5-d]imidazol-1(2H)-yl)methyl)phosphonate (4c′) white viscous oil. ¹H(400 MHz, DMSO), δ, ppm: 9.63 (s, 1H), 7.38–7.29 (m, 4H), 7.26–7.12 (m, 6H), 7.04 (d, J = 8.1 Hz, 2H), 6.99–6.91 (m, 2H), 6.78 (d, J = 8.2 Hz, 1H), 5.64 (d, J = 27.2 Hz, 1H), 5.15 (s, 2H), 2.88 (s, 3H), 2.82 (s, 3H), 2.56 (s, 3H). ¹³C NMR (101 MHz, DMSO), δ, ppm: 157.04, 156.22 (d, J = 3.7 Hz), 155.82, 128.03 (d, J = 13.3 Hz), 123.42 (d, J = 7.3 Hz), 118.81 (dd, J = 16.8, 4.1 Hz), 118.48, 117.94, 114.21, 113.79, 70.30, 69.79, 54.92 (d, J = 158.1 Hz), 28.57, 28.17, 28.14; ³¹P (162 MHz, DMSO), δ, ppm: 14.16 (d, J = 27.1 Hz). MS (HRMS-ESI): Calcd. for C₂₆H₂₇N₄O₆P, [M + H]⁺: 523.1741, found: m/z 523.1777.

Diphenyl ((1R)-(3-hydroxyphenyl)(3,4,6-trimethyl-2,5-dioxohexahydroimidazo[4,5-d]imidazol-1(2H)-yl)methyl)phosphonate (4c″) white viscous oil. ¹H(400 MHz, DMSO), δ, ppm: δ 9.67 (s, 1H), 7.54–7.34 (m, 4H), 7.30–7.20 (m, 3H), 7.20–7.15 (m, 2H), 7.15–7.04 (m, 4H), 6.78 (dd, J = 2.4, 8.1 Hz, 1H), 5.76 (d, J = 25.9 Hz, 1H), 5.49 (d, J = 8.5 Hz, 1H), 4.97 (d, J = 8.6 Hz, 1H), 2.88 (s, 3H), 2.82 (s, 3H), 2.19 (s, 3H). ¹³C NMR (101 MHz, DMSO), δ, ppm: 157.27, 155.99 (d, J = 3.1 Hz), 155.90, 147.92 (dd, J = 9.7, 6.4 Hz), 133.51 (d, J = 7.3 Hz), 128.43 (d, J = 6.5 Hz), 124.00, 118.59 (dd, J = 25.6, 4.1 Hz), 117.32 (d, J = 8.1 Hz), 113.86, 113.73 (d, J = 8.8 Hz), 70.16, 68.62, 51.47 (d, J = 155.0 Hz), 28.62, 28.12; ³¹P (162 MHz, DMSO), δ, ppm: 13.35 (d, J = 25.7 Hz); MS (HRMS-ESI): Calcd. for C₂₆H₂₇N₄O₆P, [M + H]⁺: 523.1741, found: m/z 523.1780.

Diphenyl ((1S)-(4-nitrophenyl)(3,4,6-trimethyl-2,5-dioxohexahydroimidazo[4,5-d]imidazol-1(2H)-yl)methyl)phosphonate (4d′) yellow viscous oil. ¹H (400 MHz, Chloroform-d), δ, ppm: 8.19 (2H, d, J = 8.1 Hz), 7.84 (2H, d, J = 8.2 Hz), 7.35–7.20 (4H, m), 7.21–7.02 (6H, m), 5.26 (1H, d, J = 26.4 Hz), 4.93 (2H, d, J = 5.1 Hz), 2.95 (3H, s), 2.88 (3H, s), 2.83 (3H, s); ¹³C NMR (101 MHz, Chloroform-d), δ, ppm: 158.42, 158.22 (d, J = 4.2 Hz), 150.15 (d, J = 9.7 Hz), 147.94 (d, J = 3.1 Hz), 140.66, 130.19, 129.96 (d, J = 6.0 Hz), 129.69 (d, J = 8.7 Hz), 125.97 (d, J = 28.7 Hz), 125.55 (d, J = 24.6 Hz), 123.97 (d, J = 14.4 Hz), 120.42, 120.26 (d, J = 4.3 Hz), 119.99 (d, J = 4.0 Hz), 72.77, 72.26, 57.88 (d, J = 156.2 Hz), 30.65, 30.49, 30.04; ³¹P (162 MHz, Chloroform-d), δ, ppm: 11.29 (d, J = 26.4 Hz); MS (HRMS-ESI): Calcd. for C₂₆H₂₆N₅O₇P, [M + H]⁺: 552.1643, found: m/z 552.1674.

Diphenyl ((1R)-(4-nitrophenyl)(3,4,6-trimethyl-2,5-dioxohexahydroimidazo[4,5-d]imidazol-1(2H)-yl)methyl)phosphonate (4d″) yellow viscous oil. ¹H (400 MHz, Chloroform-d), δ, ppm: 8.15 (2H, d, J = 8.2 Hz), 7.93 (2H, d, J = 7.9 Hz), 7.34–7.24 (4H, m), 7.20–7.10 (6H, m), 6.18 (1H, d, J = 26.2 Hz), 5.43 (1H, d, J = 8.6 Hz), 4.29 (1H, dd, J = 8.6, 1.4 Hz), 2.90 (2H, s), 2.82 (2H, s), 2.09 (2H, s); ¹³C NMR (101 MHz, Chloroform-d), δ, ppm: 157.03, 155.93 (d, J = 4.1 Hz), 148.27 (d, J = 9.0 Hz), 147.43 (d, J = 10.6 Hz), 146.30, 134.72 (d, J = 8.8 Hz), 132.98 (d, J = 9.2 Hz), 128.22, 128.01, 124.17, 123.84, 121.68 (d, J = 7.1 Hz), 118.46 (d, J = 4.2 Hz), 118.06 (d, J = 4.4 Hz), 70.31, 68.62, 50.53 (d, J = 158.2 Hz), 29.22, 28.69, 28.57; ³¹P (162 MHz, Chloroform-d), δ, ppm: 10.48 (d, J = 26.2 Hz); MS (HRMS-ESI): Calcd. for C₂₆H₂₆N₅O₇P, [M + H]⁺: 552.1643, found: m/z 552.1670.

Diphenyl ((1S)-(4-hydroxyphenyl)(3,4,6-trimethyl-2,5-dioxohexahydroimidazo[4,5-d]imidazol-1(2H)-yl)methyl)phosphonate (4e′) white viscous oil. ¹H(400 MHz, DMSO), δ, ppm: 9.72 (s, 1H), 7.50 (d, J = 7.8 Hz, 2H), 7.39–7.27 (m, 5H), 7.20–7.14 (m, 3H), 7.10–7.04 (m, 2H), 6.98–6.92 (m, 2H), 6.84 (d, J = 7.6 Hz, 2H), 5.63 (d, J = 26.5 Hz, 1H), 5.11 (s, 2H), 2.88 (s, 3H), 2.81 (s, 3H), 2.63 (s, 3H). ¹³C NMR (101 MHz, DMSO), δ, ppm: 157.19, 156.37 (d, J = 4.3 Hz), 155.69, 148.53 (t, J = 10.0 Hz), 129.17 (d, J = 7.3 Hz), 128.05 (d, J = 11.1 Hz), 123.42 (d, J = 5.5 Hz), 118.89 (d, J = 4.0 Hz), 118.74 (d, J = 4.0 Hz), 113.88, 70.40, 69.61, 54.34 (d, J = 160.3 Hz), 29.03, 28.55, 28.20; ³¹P (162 MHz, DMSO), δ, ppm: 14.56 (d, J = 26.3 Hz); MS (HRMS-ESI): Calcd. for C₂₆H₂₇N₄O₆P, [M + H]⁺: 523.1741, found: m/z 523.1767.

Diphenyl ((1R)-(4-hydroxyphenyl)(3,4,6-trimethyl-2,5-dioxohexahydroimidazo[4,5-d]imidazol-1(2H)-yl)methyl)phosphonate (4e″) white viscous oil. ¹H(400 MHz, DMSO), 9.70 (1H, s), 7.50 (2H, d, J = 7.8 Hz) 7.47–7.34 (5H, m), 7.24 (3H, dt, J = 14.5, 7.4 Hz), 7.16 (2H, d, J = 8.0 Hz), 7.08 (2H, d, J = 8.0 Hz), 6.81 (2H, d, J = 8.5 Hz), 5.71 (1H, d, J = 25.2 Hz), 5.48 (1H, d, J = 8.4 Hz), 4.95 (1H, d, J = 8.4 Hz), 2.85 (3H, s), 2.81 (3H, s), 2.16 (3H, s); ¹³C NMR (101 MHz, DMSO), δ, ppm: 159.34, 158.13 (d, J = 2.3 Hz), 158.02, 150.10 (dd, J = 9.9, 4.6 Hz), 130.71 (d, J = 8.6 Hz), 130.53 (d, J = 8.4 Hz), 126.06, 120.86 (d, J = 4.0 Hz), 120.60 (d, J = 4.1 Hz), 115.99, 72.27, 70.64, 53.36 (d, J = 155.0 Hz), 30.82, 30.64, 30.19; ³¹P (162 MHz, DMSO), δ, ppm:13.87 (d, J = 25.4 Hz); MS (HRMS-ESI): Calcd. for C₂₆H₂₇N₄O₆P, [M + H]⁺: 523.1741, found: m/z 523.1776.

Diphenyl ((1S)-(2-nitrophenyl)(3,4,6-trimethyl-2,5-dioxohexahydroimidazo[4,5-d]imidazol-1(2H)-yl)methyl)phosphonate (4f″) yellow viscous oil. ¹H(400 MHz, DMSO), δ, ppm: 8.24 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.86 (td, J = 1.4, 7.8 Hz, 1H), 7.73 (t, J = 7.7 Hz, 1H), 7.44–7.17 (m, 7H), 7.17–7.03 (m, 2H), 7.01–6.94 (m, 2H), 6.35 (d, J = 26.2 Hz, 1H), 5.49 (d, J = 8.4 Hz, 1H), 5.11 (d, J = 8.4 Hz, 1H), 2.84 (d, J = 5.5 Hz, 6H), 2.39 (s, 3H). ¹³C NMR (101 MHz, DMSO), δ, ppm: 159.46, 157.74, 150.21–149.95 (m), 133.92, 132.08 (d, J = 4.3 Hz), 131.19, 130.47 (d, J = 17.6 Hz), 127.62 (d, J = 7.0 Hz), 126.06 (d, J = 9.2 Hz), 125.74, 120.56 (dd, J = 21.0, 4.2 Hz), 72.48, 70.83 (d, J = 3.2 Hz), 50.04 (d, J = 158.9 Hz), 30.90, 30.76, 30.29; ³¹P (162 MHz, DMSO), δ, ppm: 11.67 (d, J = 26.4 Hz); MS (HRMS-ESI): Calcd. for C₂₆H₂₆N₅O₇P, [M + H]⁺: 552.1643, found: m/z 552.1692.

3.3. X-ray Crystallography

The X-ray diffraction data were collected at 150 °K with the Bruker D8 Venture diffractometer (Bruker Optik GmbH, Ettlingen, Germany) (0.5° ω- and φ-scans, fixed-χ three-circle goniometer, CMOS PHOTON III detector, Mo-IμS 3.0 microfocus source, focusing Montel mirrors, λ = 0.71073 Å MoK_α radiation, N₂-flow thermostat). Data reduction was performed via the APEX 3 suite. The crystal structure was solved using the ShelXT [25] and was refined using the ShelXL [26] programs assisted by the Olex2 GUI [27]. The atomic displacements for the non-hydrogen atoms were refined with harmonic anisotropic approximation. Hydrogen atoms were located geometrically and refined in the riding model.

Table 4. Crystallography data for compounds 4a’ and 4a’’.

Parameter	4a′	4a″
Empirical formula	C29H31.50N5.50O5P	C26H27N4O5P
Formula weight	568.07	506.49
Temperature, °K	150 (2)	150 (2)
Crystal system	Monoclinic	Monoclinic
Space group	C2/c	P21/c
a, Å	23.3403 (5)	19.9010 (12)
b, Å	10.3182 (2)	6.7267 (4)
c, Å	24.6303 (5)	18.6840 (13)
β, °	109.626 (1)	101.842 (2)
Volume, Å3	5587.1 (2)	2448.0 (3)
Z	8	4
ρcalc, g/cm3	1.351	1.374
μ, mm−1	0.15	0.16
F(000)	2392	1064
Crystal size, mm3	0.30 × 0.15 × 0.04	0.17 × 0.03 × 0.02
2Θ range for data collection, °	4.36–62.0	4.45–50.13
Index ranges	−29 ≤ h ≤ 32 −14 ≤ k ≤ 14 −32 ≤ l ≤ 35	−20 ≤ h ≤ 23 −7 ≤ k ≤ 8 −19 ≤ l ≤ 22
Reflections collected	44,831	15,374
Independent reflections	8204	4314
Parameters	372	328
Goodness-of-fit on F2	1.039	0.971
Final R indexes [I ≥ 2σ (I)]	R1 = 0.0417, wR2 = 0.1133	R1 = 0.0417, wR2 = 0.1133
Final R indexes [all data]	R1 = 0.0517, wR2 = 0.1208	R1 = 0.0517, wR2 = 0.1208
Largest diff. peak/hole, e·Å−3	0.42, −0.56	0.24, −0.37

represents the crystallographic parameters for compounds 4a′ and 4a″.

3.4. HPLC Analysis

The analysis was performed with the Agilent 1200 chromatograph (Agilent Technologies, Santa Clara, CA, USA). Spectrophotometric detection was carried out using the Zorbax Eclipse Plus C18 4.6 × 100 mm 3.5 μm chromatographic column (Agilent Technologies, Santa Clara, CA, USA) as a stationary phase. The chromatographic mode was gradient, mobile phase A was a buffer solution (25 mM formic acid (Honeywell Fluka, Charlotte, NC, USA) and 5 mM ammonia (Honeywell Fluka, Charlotte, NC, USA)), and mobile phase B was acetonitrile (PanReac AppliChem, Darmstadt, Germany). Gradient mode: 0.0 min–50% A, 0.5 min–50% A, 7.5 min–20% A, 9.0–20% A, 9.01–50% A, 11.0–50% A. Flow rate was 1.5 mL/min, and thermostat temperature was 25 °C.

3.5. Preparative HPLC

The preparative purification and separation of diastereomers 4a′–e′ and 4a″–f″ were performed using the Shimadzu LC 20 Prominence chromatograph (Shimadzu, Kyoto, Japan) with the Kromasil C18 column 20 × 250 mm, 5 µm particle size (Nouryon, Bohus, Sweden). The column temperature was set to 25 °C (±1 °C). The mobile phase consisted of a water–acetonitrile mixture (60:40). The flow rate was 5 mL/min in the isocratic mode. The detection wavelength for the UV detector equaled 250 nm. The samples were preliminarily dissolved in acetonitrile (1:10, v/v). Figures S48–S53 (Supplementary Materials) show the HRMS of the compounds 4a–4f.

3.6. HRMS

The analysis was performed using the HPLC-MS method in the electro-spray ionization mode using the Agilent QTOF-6550 (Agilent Technologies, Santa Clara, CA, USA) connected with Agilent 1260 Infinity II (Agilent Technologies, Santa Clara, CA, USA). The samples were analyzed with the Poroshell 120 EC-C18 column 2.1 × 100 mm, 2.7 µm particle size. The column temperature was set as 30 °C (±0.4 °C). The chromatographic analysis was performed in isocratic mode. The 0.05% formic acid (Honeywell Fluka, Charlotte, NC, USA) aqueous solution–acetonitrile mixture (60:40) was applied as a mobile phase. The flow rate was 0.5 mL/min. The samples were analyzed in a positive ionization mode with a scan range of 300–900 Da. Capillary and nozzle voltages were set to 2000 and 100 V, respectively. Drying gas temperature was 200 °C, and sheath gas temperature was 250 °C. The drying gas flow was 13 L/min, and the sheath gas flow was 11 L/min. The samples were preliminarily dissolved in acetonitrile (1:1000, v/v). Figures S37–S47 (Supplementary Materials) show the preparative elution profiles of the compounds 4a–4f.

3.7. Computational Details

All model calculations were performed using the Gaussian’09 program package [28] installed on the SKIF “Cyberia” supercomputer of Tomsk State University. The geometries of the structures under analysis were fully optimized at the meta-hybrid functional M062X [29] with the split-valence basis set 6-311+G(2d,p) in DMSO (ε = 46.826) as a solvent using PCM. The PCM was applied using a scaled van der Waals surface cavity with an alpha value of 1.1, and atomic radii modelling using a universal forcefield. The geometry optimization was performed on the basis of the experimentally determined X-ray structures of 4a’ and 4a″ without conformational analysis. Frequency calculations were also performed at the M062X/6-311+G(2d,p) level of theory. The freely available GoodVibes script developed by Paton and Funes-Ardoiz [30] was used to recalculate the thermochemical data with the low-frequency corrections and correction from the gas with the pressure of 1 atm to solution with the concentration of 1 mol/L.

Tables S3–S6 (Supplementary Materials) show the correlation between the geometric parameters for the optimized 4a molecular structures and the experimental data. Table S7 (Supplementary Materials) presents the XYZ coordinates for all of the compounds under analysis.

Magnetic shielding tensors were calculated with the gauge including atomic orbitals (GIAO) DFT method using the Gaussian’09 at the PBE0/6-311+G(2d,p) level theory.

The chemical shifts (δ ³¹Pcalc) were detected as δ ³¹Pcalc = σ H₃PO₄–σ calc, where σ H₃PO₄ is the shielding constant of ³¹P in phosphoric acid (H₃PO₄). The σ H₃PO₄ values of ³¹P of the H₃PO₄ were computed using the same strategy as for structure 4. Figure S54 (Supplementary Materials) shows the correlations between experimental and calculation values δ ¹H, ¹³C atoms of 3a, 6a, CHPO₃ and δ ³¹P of the compounds 4a–4f.

4. Conclusions

The results demonstrate an approach to the synthesis of new phosphonate derivatives of 1,3,4-trimethylglycoluril via the Birum–Oleksyszyn reaction. This approach allowed for the obtainment of a series of diastereomers that were formed in the reaction medium with the predominance of structure 4″. The obtained diastereomers can be separated by the preparative HPLC with the C18 stationary phase. The diastereomers’ structures were confirmed via NMR spectroscopy and HRMS; for compound 4a, the structure was confirmed with a single-crystal X-ray diffraction analysis. The results of the quantum chemical calculations were consistent with the experimental data. Additionally, the authors revealed a correlation between the spatial arrangement of substituents in the structure of 1-[aryl-(diphenylphosphono)methyl]-3,4,6-trimethylglycolurils and the δ values of the proton on the carbon atom in the phosphonate group (CHPO₃) as well as the proton bridging CH-CH group. For the compounds with structure 4′, the signals of the methine protons in the CH-CH bond were recorded in the ¹H NMR spectrum as two doublets within the narrow region (5.11–5.37 ppm), while for the compounds with structure 4″, the signals of these protons were recorded within a wider range (4.95–5.51 ppm). At the same time, the signal of the proton bonded to the carbon atom in the phosphonate group (CHPO₃) was shifted to a higher field for the compounds with structure 4′ compared to the similar proton in structure 4″.