Synthesis and Structure of 1-Substituted Semithioglycolurils

Abstract

Two methods for the synthesis of previously unavailable 1-substituted semithioglycolurils were developed. These methods consist of the cyclocondensation of 1-substituted ureas with 4,5-dihydroxy- or 4,5-dimethoxyimidazolidine-2-thione or glyoxal, followed by the reaction of the resulting 1-substituted 4,5-dihydroxyimidazolidine-2-ones with HSCN in a two-step one-pot procedure. Two of the desired semithioglycolurils were obtained as conglomerates.

Key words

semithioglycolurils - cyclocondensation - heterocycles - urea derivatives - thiourea derivatives - glyoxal

Since the first synthesis of a glycoluril, published by Hugo Schiff in 1877,[1] the chemistry of these compounds has been actively developing. Hundreds of glycolurils with different combinations of substituents at nitrogen and carbon atoms have been synthesized.[2] [3] [4] [5] Thio-, amino-, and sulfo-based analogues of glycolurils are less available.[2,6] More and more research has focused on semithioglycolurils I–IX (Figure [1]),[2] ^, [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] including compounds I, II, V, VII, and VIII that were synthesized in our laboratory.[6] ^, [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26]

Figure 1 Previously reported semithioglycolurils

Although a wide range of trisubstituted semithioglycolurils I and II have been reported, they are still actively investigated, as some of them have antifungal and cytotoxic activities.[12] [13] Other compounds III–IX are represented by several examples and used as scaffolds in the synthesis of semithiobambusurils (III and VII),[11] [27] in Claisen condensation matrices (IV),[10] and in the synthesis of tri-, tetra-, and polycyclic systems (V)[28] [29] [30] [31] and iminoglycolurils (V, VII, VIII).[6] Methods for the preparation of a small number of compounds III–IX reported in the literature are underdeveloped. The focus of this article is on a methodology for the synthesis of 1-substituted semithioglycolurils.

Semithioglycolurils have so far been represented by only three examples (Scheme [1]).[6] [14] [25] Compounds 1a,b were obtained by the reaction of 1-alkylureas 2a,b with 4,5-dimethoxyimidazolidine-2-thione (DMIT; 3) or 4,5-dihydroxyimidazolidine-2-thione (DHIT; 4) (approach 1).[6] [25] Semithioglycoluril 1c was prepared by the condensation of 1-cyclohexyl-4,5-dihydroxyimidazolidin-2-one (5a) with KSCN and hydrochloric acid (approach 2).[14] Here, these approaches were studied in detail, and two methods for the synthesis of 1-substituted semithioglycolurils were developed.

Scheme 1 Two approaches for the synthesis of 1-alkyl-substituted semithioglycolurils 1a–c

To develop approach 1, we started with the reactions of DMIT (3) and DHIT (4) with ethylurea (2c) in water by varying the amount of hydrochloric acid (pH 1) and time used for heating the reaction mixture (10 min, 30 min, 1 h, and 2 h) at 76–80 °C (Table [1]). By ¹H NMR monitoring of dried reaction mixture aliquots, the dependence of the conversion of ethylurea (2c) into thioglycoluril 1d on the reaction conditions was analyzed. The conversion rate was estimated by analyzing the proton signals of the Me groups of urea 2c (t, δ = 0.96) and thioglycoluril 1d (t, δ = 1.02) and the CH–CH group of thioglycoluril 1d (d, δ = 5.46). It was established that the conversion of 2c to 1d is 33% and 37% when the reaction of urea 2c with DMIT (3) is carried out with hydrochloric acid (0.027 mL) for 30 minutes and 1 hour, respectively (Table [1], entries 1, 2).

Table 1 Screening of Conditions for the Synthesis of Thioglycoluril 1d (Approach 1)^a

Entry	Reagents (ratio)	Aq HCl (35%) (mL)	Time	Conversion (%)b
1	2c, 3 (1:1)	0.027	30 min	33
2	2c, 3 (1:1)	0.027	1 h	37
3	2c, 3 (1:1)	0.08	10 min	41
4	2c, 3 (1:1)	0.08	30 min	59
5	2c, 3 (1:1)	0.08	1 h	64
6	2c, 3 (1:1)	0.08	2 h	64
7	2c, 4 (1:1)	0.08	10 min	52
8	2c, 4 (1:1)	0.08	30 min	64
9	2c, 4 (1:1)	0.08	1 h	65
10	2c, 4 (1:1)	0.08	2 h	65
11	2c, 4 (1:1.5)	0.08	30 min	65
12	2c, 4 (1:1.2)	0.08	30 min	71c

^a Reaction conditions: 2c (2.5 mmol, 1 equiv), 3 or 4, H₂O (10 mL), aq HCl (35%), 76–80 °C.

^b Conversion of 2с into 1d according to ¹H NMR spectroscopy.

^c Reaction conditions: 2c (0.22 g, 2.5 mmol), 4 (0.40 g, 3.0 mmol), H₂O (10 mL), aq HCl (35%, 0.08 mL), 76–80 °C, 30 min.

When the volume of hydrochloric acid (0.08 mL) was increased, the conversion of 2c into 1d increased to 41 and 64%, for 10 minutes and 1 hour of reaction time, respectively (Table [1], entries 3 and 5), and remained constant even after 2 hours of reaction (entry 6). Similar results were observed when we used DHIT (4); however, the reaction rate of forming semithioglycoluril 1d increased. After 10 minutes, the conversion of 2c into 1d was 52% (entry 7), and increased to 64% after 30 minutes (entry 8). Therefore, it is more efficient to use DHIT (4) rather than DMIT (3), with a reaction time of 30 minutes. Apart from that, we noticed that DHIT (4) is partially consumed in a competing reaction to produce the earlier reported 2-thioxoimidazolidin-4-one (thiohydantoin)[32] (the most characteristic signal of CH₂ protons: s, δ = 4.06); we also detected ethylurea (2c) in the reaction mixture.

For a more complete transformation of ethylurea (2c) into semithioglycoluril 1d, we used a larger amount of DHIT (4) (1.2 and 1.5 equiv; Table [1], entries 12 and 11, respectively). ¹H NMR monitoring of this reaction showed that the conversion of 2c into 1d was 65% with DHIT (1.5 equiv) after 30 minutes of heating, but DHIT was still present in the resulting product (entry 11). The use of DHIT (4; 1.2 equiv) in this reaction led to an increase of the conversion of ethyl­urea (2c) to thioglycoluril 1d up to 71% after 30 minutes (entry 12). The yield of thioglycoluril 1d was 52% after its purification (Table [2], approach 1, entry 3). Thus, the best yield of thioglycoluril 1d was achieved in the reaction of DHIT (4; 2.5 mmol, 1 equiv) with ethylurea (2c) in a 4/2c ratio of 1.2:1 in water with 35% hydrochloric acid (0.08 mL) at 76–80 °С for 30 min (Table [1], entry 12).

Table 2 Comparison of Two Approaches to the Synthesis of Semithioglycolurils 1a–p

Entry	R	Urea	DHI	Product	Yield (%) of 1 by approach 1a	Yield (%) of 1 by approach 2b,c
1	Me	2a	5b	1a	51	31b
2	i-Pr	2b	5c	1b	50	52b
3	Et	2c	5d	1d	52	58b
4	Pr	2d	5e	1e	20	55b
5	t-Bu	2e	5f	1f	61	50b
6	Cy	2f	5a	1c	65	9d
7	CH2 c-C3H5	2g	5g	1g	45	53b
8	(CH2)2OH	2h	5h	1h	26	54b
9	(CH2)3OH	2i	5i	1i	15	0 (1i)b, 9 (6)b
10	Me2CCH2OH	2j	5j	1j	41	45b
11	All	2k	5k	1k	40	62c
12	Bn	2l	5l	1l	45	63c
13	PMB	2m	5m	1m	46	65c
14	(CH2)2Ph	2n	5n	1n	–	61c
15	Ph	2o	–	1o	34	–
16	(CH2)3CO2H	2p	5p	1p	36	–

^a Reaction conditions: 2 (2.5 mmol), 4 (0.40 g, 3.0 mmol), H₂O (10 mL), aq HCl (35%, 0.08 mL), 76–80 °C, 30 min.

^b Reaction conditions: 1. 2 (20 mmol), glyoxal hydrate trimer (1.61 g, 7.7 mmol), H₂O (10 mL), NaOH (to pH 10), 50–55 °C, 3 h. 2. MeOH (20 mL), NaSCN (3.65 g, 45 mmol), aq HCl (35%, 4.4 mL); NaCl precipitate removed by filtration; filtrate refluxed, 30 min.

^c Reaction conditions: 1. 2 (20 mmol), glyoxal hydrate trimer (1.61 g, 7.7 mmol), i-PrOH (10 mL), reflux, 5 h. 2. MeOH (20 mL), NaSCN (3.65 g, 45 mmol), aq HCl (35%, 4.4 mL); NaCl precipitate removed by filtration; filtrate refluxed, 30 min.

^d Total yield of 1c [5a: 12% (stage 1),[33] 1c: 74% (stage 2)[14]].

The target glycolurils 1a–m,o,p were synthesized in 15–65% yield by using the optimized conditions of condensation of DHIT (4) with 1-substituted ureas 2a–m,o,p (Table [2], approach 1, entries 1–13, 15, 16). In total, 15 compounds were synthesized by approach 1.

As 1-cyclohexyl-DHI 5a had been prepared before,[32] approach 2 made use of the condensation of DHI 5 with NaSCN­ and hydrochloric acid, so that 1-substituted DHI 5b–o had to be prepared (Table [2]). To do so, a model reaction of ethylurea (2c) and glyoxal was examined under the same conditions that were used for the synthesis of 1,3-dimethyl-DHI, with H₂O as the solvent, at pH 10 and 50–55 °C.[34] The next goal was to determine the reaction time needed for ethylurea 2с to completely transform into DHI 5d. We used ¹H NMR monitoring of dried reaction mixture aliquots (after 5 min, 1 h, 2 h and 3 h; Figure [2]). It was established that the conversion of urea 2c into DHI 5d was complete after­ 3 hours. After this time, the signals of the protons of urea 2c disappeared, while new signals of the DHI protons appeared in the ¹H NMR spectrum (Figure [2d]). As no side products were detected (Figure [2d]), we used a reaction mixture in the reaction with NaSCN and hydrochloric acid, without isolation of DHI 5d (as well as of DHI 5b,c,e–h,j). Target compound 1d was obtained in 58% yield (Table [2], approach 2, entry 3). Condensation of ureas 2a–e,g,h,j with glyoxal was carried out in water for 3 hours at 50–55 °C. As a result, we synthesized a series of thioglycolurils 1a,b,d,e,f,g,h,j in 31–58% yield (Table [2], approach 2, entries 1–5, 7, 8, 10). It turned out that DHI 5i,p do not produce semithioglycolurils 1i,p (entries 9, 16). Imidazooxazine 6 was isolated in 9% yield instead of product 1i (entry 9), although signals of the protons of compound 1i were found in a ¹H NMR spectrum of the reaction mixture.

Figure 2 Conversion of ethylurea (2c) into DHI 5d, followed by ¹H NMR spectra (DMSO-d ₆) of ethylurea (2c) (a) and the reaction mixture after 10 min (b), 2 h (c), and 3 h (d).

As ureas 2k–o do not dissolve in H₂O, it was necessary to develop another synthetic approach to DHI 5k–n. As a model reaction, we chose the reaction between 1-benzyl­urea 2l and glyoxal. The reaction was carried out in MeOH or i-PrOH at pH 7 or 10 (Table [3]). Reaction progress was again monitored by ¹H NMR spectroscopy. The best results were achieved in refluxing i-PrOH at pH 7. Under these conditions, a 100% conversion of urea 2l to DHI 5l (Table [3], entry 9; see also Supporting Information, SI, Figure []S1) was observed, so there was no need to isolate DHI 5l for the following reaction with NaSCN and hydrochloric acid. Target thioglycoluril 1l was synthesized in 63% yield (Table [2], approach 2, entry 12). The same methodology was applied for the synthesis of DHI 5k,m,n and semithioglycolurils 1k,m,n (yields 61–65%) (entries 11, 13, 14). Urea 2o did not produce DHI 5o, and it was separated from the reaction mixture without any change.

Table 3 Screening of Conditions for the Synthesis of DHI 5l (Approach 2)^a

Entry	Solvent	pH	Time (h)	Conv. (%)b
1	MeOH	7	1	15
2	MeOH	7	2	20
3	MeOH	7	3	24
4	MeOH	7	4	25
5	i-PrOH	7	1	59
6	i-PrOH	7	2	71
7	i-PrOH	7	3	77
8	i-PrOH	7	4	85
9	i-PrOH	7	5	100c
10	i-PrOH	10	3	33

^a Reaction conditions: 2l (2 mmol), glyoxal hydrate trimer (0.8 mmol), reflux­.

^b Conversion of 2l into 5l according to ¹H NMR spectroscopy.

^c Reaction conditions: 2l (0.30 g, 2 mmol), glyoxal hydrate trimer (0.16 g, 0.8 mmol), i-PrOH (5 mL), reflux, 5 h.

Semithioglycolurils 1i,o,p can be synthesized only by approach 1, while compound 2n can only be obtained by approach 2 (Table [2]). The yields of semithioglycolurils 1e,g,h,k–m from approach 2 are 8–35% higher. For compounds 1a,c,f, the approach 1 resulted in higher yields (by 11–56%). The yields of compounds 1b,d,j were almost the same (50–52%, 52–58%, 41–45%, respectively), so that they can be synthesized by either of the proposed two methods.

The formation of the target semithioglycolurils 1 was unambiguously confirmed by X-ray diffraction data collected for 1a,b,d,j (SI, Figures S2 and S3), which revealed two conglomerates (1a and 1j crystallized in the P2₁2₁2₁ space group) and two racemates (1b and 1d crystallized in the C2/c space group) among these semithioglycololurils. Of the four, only 1j has a substituent at one of its nitrogen atoms, the C(Me)₂CH₂OH group, which is able to form a hydrogen bond; however, its resulting crystal structure is isostructural with the one for 1a with the methyl group in the same position of the urea. In both cases, the formation of a conglomerate can be attributed to homochiral chains of semithioglycoluril molecules (SI, Figure S4), held together by hydrogen bonds of the NH groups that are on the opposite side of the molecule from the above substituent (N···O 2.820(3) Å, NHO 178(1)° and N···S 3.406(2) Å, NHS 173(1)° in 1a and N···O 2.765(5) Å, NHO 176(1)° and N···S 3.464(4) Å, NHS 172(1)° in 1j). The third NH group links these homochiral chains (N···O 2.834(3) Å, NHO 163(1)° in 1a and N···O 3.018(5) Å, NHO 167(1)° in 1j), which are rotated to each other by ca. 90° to result in a non-centrosymmetric hydrogen-bonded 3D framework. The OH group in 1j is involved in an intramolecular hydrogen bond with an adjacent oxygen atom O(1) (O···O 2.614(5) Å, OHO 156(1)°) and in a hydrogen bond with the third NH group from the molecule in a perpendicular chain, as the oxygen atom O(1) in 1a does (see above). In contrast, the semithioglycololurils 1b and 1d (SI, Figure S5) form centrosymmetric dimers through N–H···S hydrogen bonds (N···S 3.358(6) Å, NHS 160(1)° in 1b and N···S 3.569(3) Å, NHS 149(1)° in 1d). They assemble chiral chains produced by an N–H···O hydrogen bond (N···O 2.874(8) Å, NHO 177(1)° in 1b and N···O 2.885(4) Å, NHO 144(1)° in 1d) of the NH group that is on the same side of the molecule as the above substituents, into centrosymmetric sheets. Additionally stabilized by N–H···S hydrogen bonds formed the third NH group in 1b (N···S 3.464(6) Å, NHS 156(1)°), those are held together by weak van der Waals interactions. In 1d, the same NH group is involved in an N–H···S hydrogen bond with the neighboring chiral chain (N···S 3.564(3) Å, NHS 137(1)°), thus completing a centrosymmetric hydrogen-bonded 3D framework. As a result, the semithioglycolurils 1b and 1d were crystallized as racemates (SI, Table S1), and 1a and 1j, as conglomerates. A possible explanation for this behavior is that the isopropyl and ethyl substituents are diverted towards the NH group in the former two compounds, somehow favoring the centro­symmetric arrangement of their molecules.

In summary, reactions of 1-substituted ureas with 4,5-dihydroxy- or 4,5-dimethoxyimidazolidine-2-thione (approach 1) or with glyoxal, using the resulting 1-substituted 4,5-dihydroxyimidazolidine-2-ones, with NaSCN and hydrochloric acid in a two-step one-pot procedure (approach 2) were studied in detail by ¹H NMR spectroscopy. As a result of this comprehensive study, two new methods for the synthesis of 1-substituted semithioglycolurils were developed to provide 16 different products, 13 of which were reported for the first time. Two of these compounds produced the first conglomerates reported for semithioglycolurils, as unambiguously identified by X-ray diffraction. This research has made 1-substituted semithioglycolurils available, so that they can now be used in the synthesis of new heterocyclic compounds.

All reagents were purchased from commercial sources and used without further treatment, unless otherwise indicated. ¹H and ¹³C NMR spectra were recorded at 25–29 °C with a Bruker AM300 and Bruker DRX500 spectrometer and TMS as internal standard. HRMS (ESI) data were collected using a Bruker micrOTOF II mass spectrometer. 1-Methyl- and 1-isopropyl-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one (1a,b) were synthesized earlier from 1-methyl- and 1-isopropylurea and 3 (DMIT).[6] [25] 1-Cyclohexyl-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one (1c) was prepared earlier from 1-cyclohexyl-4,5-dihydroxyimidazolidine-2-one, KSCN, and HCl.[14] 1-Alkylureas 2b,[35] 2с,[36] 2e,[37] 2f,[35] 2h,[38] 2i,[39] 2j,[38] and 2p [38] were synthesized by previously reported procedures from the corresponding amines, hydrochloric acid, and KOCN. 1-Phenethylurea (2n)[40] was synthesized from 2-phenylethanamine, hydrochloric acid, and urea. 4,5-Dimethoxyimidazolidine-2-thione (3) was prepared from 4,5-dihydroxyimidazolidine-2-thione (4), MeOH, and hydrochloric acid.[32] 4,5-Dihydroxyimidazolidine-2-thione was synthesized by the condensation of thiourea with 40% aq glyoxal.[41]

Thioglycolurils 1a–m,o,p; Approach 1

4,5-Dihydroxyimidazolidine-2-thione (4; 0.40 g, 3.0 mmol) and the appropriate urea 2a–m,o,p (2.5 mmol) were suspended in H₂O (10 mL). Aq HCl (35%, 0.08 mL) was added, and the solution was heated to 76–80 °C and stirred for 30 min. The next day, the resulting precipitate was collected by filtration and air-dried (for 1a–k,p). The resulting precipitates of 1l,m,o were purified by recrystallization (EtOH).

Thioglycolurils 1a,b,d–h,j ; Approach 2

A mixture of the appropriate 1-alkylurea 2a–e,g–j (20 mmol), glyoxal hydrate trimer (1.61 g, 7.7 mmol), and H₂O (10 mL) was heated to 50–55 °C. Aq NaOH was added dropwise until pH 10 was reached by the reaction mixture, which was then stirred for 3 h. MeOH (20 mL), NaSCN­ (3.65 g, 45 mmol), and 35% aq HCl (4.4 mL) were added to the reaction mixture. The precipitate was removed by filtration and washed with MeOH (5 mL). The filtrate was refluxed for 30 min. Then the reaction mixture was cooled to r.t.

For 1h: The next day, the resulting precipitate of thioglycoluril 1h was collected by filtration, washed with MeOH, and dried in air.

For 1a,b,d–g: The reaction mixture was evaporated to dryness, after which CHCl₃ (10 mL) was added under stirring. The precipitate was collected by filtration and washed with H₂O (5 mL).

For 1j: The reaction mixture of 1j was evaporated to dryness, and then the resulting mixture was dissolved in H₂O (10 mL) and CHCl₃ (15 mL). The organic layer was collected and then evaporated to dryness. After the addition of MeOH (5 mL), the precipitate was collected by filtration and air-dried.

Thioglycolurils 1k–n; Approach 2

A mixture of the appropriate 1-alkylurea 2k–n (20 mmol), glyoxal hydrate trimer (1.61 g, 7.7 mmol), and i-PrOH (10 mL) was heated to reflux and stirred for 5 h. MeOH (20 mL), NaSCN (3.65 g, 45 mmol), and 35% aq HCl (4.4 mL) were added to the reaction mixture. The precipitate was removed by filtration and washed with MeOH (5 mL). The filtrate was refluxed for 30 min. Then the reaction mixture was cooled to r.t. The resulting precipitate was collected by filtration and air-dried.

1-Methyl-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one (1a)[6]

Beige powder; yield: 0.22 g (51%) (approach 1); brown crystals; yield: 1.07 g (31%) (approach 2); mp 283–285 °С (MeOH) (283–285 °С (H₂O)[6]).

1-Isopropyl-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one (1b)[25]

Beige powder; yield: 0.25 g (50%) (approach 1); brown crystals; yield: 2.08 g (52%) (approach 2); mp 260–261 °С (MeOH) (260–261 °С (H₂O)[25]).

IR (KBr): 2975, 2894, 1677, 1533, 1492, 1337, 1225, 1210, 1105, 880, 755, 634, 586 cm^–1.

¹H NMR (300 MHz, DMSO-d ₆): δ = 0.61 (d, ³ J = 6.6 Hz, 6 Н, Me), 3.78–3.92 (m, 1 H, CH), 5.37 (d, ³ J = 8.4 Hz, 1 Н, CH), 5.52 (d, ³ J = 8.5 Hz, 1 Н, CH), 7.42 (s, 1 H, NH), 8.99 (s, 1 H, NH), 9.04 (s, 1 H, NH).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 18.98, 21.42 (Me), 43.20 (CH), 66.61, 69.87 (CH–CH), 158.34 (C=O), 182.80 (C=S).

HRMS (ESI): m/z [M + H]⁺ calcd for C₇H₁₂N₄OS + H: 201.0805; found: 201.0805.

1-Cyclohexyl-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one (1c)[14]

Beige powder; yield: 0.39 g (65%) (approach 1); mp 294–296 °C (H₂O) (294–296 °С (H₂O)[14]).

1-Ethyl-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one (1d)

Beige powder; yield: 0.24 g (52%) (approach 1); brown crystals; yield: 2.15 g (58%) (approach 2); mp 256–258 °С (MeOH).

IR (KBr): 3348, 3185, 2980, 2877, 1680, 1527, 1489, 1341, 1309, 1251, 1099, 887, 585 cm^–1.

¹H NMR (300 MHz, DMSO-d ₆): δ = 1.02 (t, ³ J = 7.1 Hz, 3 Н, Me), 3.01 (dq, ² J = 14.2 Hz, ³ J = 7.1 Hz, 1 H, CH₂), 3.26 (dq, ² J = 14.4 Hz, ³ J = 7.2 Hz, 1 H, CH₂), 5.37 (d, ³ J = 8.4 Hz, 1 Н, CH), 5.46 (d, ³ J = 8.4 Hz, 1 Н, CH), 7.49 (s, 1 H, NH), 9.02 (s, 1 H, NH), 9.15 (s, 1 H, NH).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 12.83 (Me), 35.09 (CH₂), 66.31, 71.1 (CH–CH), 158.46 (C=O), 182.74 (C=S).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₆H₁₀N₄OS + Na: 209.0468; found: 209.0464.

1-Propyl-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one (1e)

Beige powder; yield: 0.10 g (20%) (approach 1), 2.20 g (55%) (approach 2); mp 243–245 °С (MeOH).

IR (KBr): 2967, 2932, 2879, 1682, 1531, 1492, 1250, 1206, 1100, 886 cm^–1.

¹H NMR (300 MHz, DMSO-d ₆): δ = 0.61 (t, ³ J = 7.3 Hz, 3 Н, Me), 1.37–1.57 (m, 2 H, CH₂), 2.91–3.00 (m, 1 H, CH₂), 3.08–3.33 (m, 1 H, CH₂), 5.38 (d, ³ J = 8.5 Hz, 1 Н, CH), 5.44 (d, ³ J = 8.5 Hz, 1 Н, CH), 7.45 (s, 1 H, NH), 8.98 (s, 1 H, NH), 9.11 (s, 1 H, NH).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 11.07 (Me), 20.31, 41.91 (CH₂), 66.27, 71.45 (CH–CH), 158.66 (C=O), 182.71 (C=S).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₇H₁₂N₄OS + Na: 223.0624; found: 223.0627.

1-tert-Butyl-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one (1f)

Violet powder; yield: 0.33 g (61%) (approach 1); beige powder; yield: 2.61 g (50%) (approach 2); mp 278–280 °С (H₂O).

IR (KBr): 3182, 2974, 2900, 1687, 1535, 1487, 1254, 1214, 1158, 775, 744 cm^–1.

¹H NMR (300 MHz, DMSO-d ₆): δ = 1.32 (s, 9 Н, Me), 5.25 (d, ³ J = 8.3 Hz, 1 Н, CH), 5.65 (d, ³ J = 8.3 Hz, 1 Н, CH), 7.33 (s, 1 H, NH), 8.99 (s, 2 H, NH).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 29.10 (Me), 53.52 (C), 66.63, 72.75 (CH–CH), 159.83 (C=O), 184.09 (C=S).

HRMS (ESI): m/z [M + H]⁺ calcd for C₈H₁₄N₄OS + H: 215.0961; found: 215.0962.

1-(Cyclopropylmethyl)-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one (1g)

Beige powder; yield: 0.24 g (45%) (approach 1), 2.25 g (53%) (approach 2); mp 249–250 °С (MeOH).

IR (KBr): 3346, 3171, 3007, 2872, 1680, 1524, 1486, 1334, 1520, 1199, 1097, 1060, 1020, 886,724 cm^–1.

¹H NMR (300 MHz, DMSO-d ₆): δ = 0.08–0.14 (m, 1 H, CH₂), 0.28–0.50 (m, 3 H, CH₂), 0.83–0.96 (m, 1 H, CH), 2.68 (dd, ² J = 14.3 Hz, ³ J = 7.7 Hz, 1 H, CH₂), 3.22 (dd, ² J = 13.6 Hz, ³ J = 7.2 Hz, 1 H, CH₂), 5.41 (d, ³ J = 8.4, Hz, 1 H, CH), 5.58 (d, ³ J = 8.3, Hz, 1 H, CH), 7.51 (s, 1 H, NH), 9.01 (s, 1 H, NH), 9.15 (s, 1 H, NH).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 3.29, 3.96 (CH₂), 9.31 (CH), 44.62 (CH₂), 66.37, 71.39 (CH–CH), 158.57 (C=О), 182.79 (C=S).

HRMS (ESI): m/z [M + H]⁺ calcd for C₈H₁₂N₄OS + H: 213.0810; found: 213.0807.

1-(2-Hydroxyethyl)-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one (1h)

Beige thin needles; yield: 0.13 g (26%) (approach 1), 2.18 g (54%) (approach 2); mp 250–252 °С (MeOH).

IR (KBr): 3409, 3247, 2886, 2055, 1730, 1501, 1322, 1243, 1196, 1047, 876, 757 cm^–1.

¹H NMR (300 MHz, DMSO-d ₆): δ = 3.08 (dt, ² J = 14.2 Hz, ³ J = 5.7 Hz, 1 Н, CH₂), 3.24 (dt, ² J = 14.1 Hz, ³ J = 6.1 Hz, 1 Н, CH₂), 3.47 (t, ³ J = 5.9 Hz, 2 Н, CH₂), 4.45–5.11 (br. s, 1 Н, OH), 5.38 (d, ³ J = 8.4 Hz, 1 Н, CH), 5.49 (d, ³ J = 8.3 Hz, 1 Н, CH), 7.53 (s, 1 H, NH), 8.99 (s, 1 H, NH), 9.04 (s, 1 H, NH).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 42.94, 58.68 (CH₂), 66.31, 72.17 (CH–CH), 158.75 (C=O), 182.63 (C=S).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₆H₁₀N₄O₂S + Na: 225.0417; found: 225.0417.

1-(3-Hydroxypropyl)-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one (1i)

Beige powder; yield: 0.08 g (15%) (approach 1); mp 222–225 °С (H₂O).

IR (KBr): 3421, 3317, 1680, 1528, 1494, 1249, 1203, 1094, 1058, 884 cm^–1.

¹H NMR (300 MHz, DMSO-d ₆): δ = 1.55–1.68 (m, 2 Н, CH₂), 3.03 (dt, ² J = 14.0 Hz, ³ J = 6.8 Hz, 1 Н, CH₂), 3.26 (dt, ² J = 14.0 Hz, ³ J = 7.0 Hz, 1 Н, CH₂), 3.39 (t, ³ J = 6.2 Hz, 2 Н, CH₂), 5.38 (d, ³ J = 8.3 Hz, 1 Н, CH), 5.44 (d, ³ J = 8.4 Hz, 1 Н, CH), 7.49 (s, 1 H, NH), 9.01 (s, 1 H, NH), 9.12 (s, 1 H, NH).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 35.45, 37.71, 58.39 (CH₂), 66.29, 71.62 (CH–CH), 159.72 (C=O), 182.72 (C=S).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₈H₁₂N₄O₂S + Na: 238.0573; found: 238.0567.

1-(1-Hydroxy-2-methylpropan-2-yl)-5-thioxohexahydroimidazo-[4,5-d]imidazol-2(1H)-one (1j)

Beige powder; yield: 0.24 g (41%) (approach 1), 2.07 g (45%) (approach 2); mp 264–266 °С (MeOH).

IR (KBr): 3200, 2065, 1693, 1533, 1489, 1339, 1249, 1203, 1061, 888 cm^–1.

¹H NMR (300 MHz, DMSO-d ₆): δ = 1.26 (s, 6 Н, Me), 3.37 (d, ² J = 10.9 Hz, 1 Н, CH₂), 3.64 (d, ² J = 10.7 Hz, 1 Н, CH₂), 4.77–5.14 (br. s, 1 Н, OH), 5.28 (d, ³ J = 8.4 Hz, 1 Н, CH), 5.67 (d, ³ J = 8.4 Hz, 1 Н, CH), 7.38 (s, 1 H, NH), 8.83 (s, 1 H, NH), 9.00 (s, 1 H, NH).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 24.21, 24.29 (Me), 57.55 (CH₂), 66.92, 73.16 (CH–CH), 67.82 (CMe₂), 160.16 (C=O), 183.93 (C=S).

HRMS (ESI): m/z [M + H]⁺ calcd for C₈H₁₄N₄O₂S + H: 231.0910; found : 231.0905.

1-Allyl-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one (1k)

Beige powder; yield: 0.20 g (40%) (approach 1); white powder; yield: 2.45 g (62%) (approach 2); mp 245–247 °С (MeOH).

IR (KBr): 3200, 2879, 1719, 1529, 1490, 1340, 1294, 1245, 1201, 1115, 1049, 885, 678 cm^–1.

¹H NMR (300 MHz, DMSO-d ₆): δ = 3.49 (dd, ² J = 15.9 Hz, ³ J = 6.8 Hz, 1 H, CH₂), 3.92 (dd, ² J = 15.5 Hz, ³ J = 3.7 Hz, 1 H, CH₂), 5.08–5.25 (m, 2 H, CH₂), 5.37 (q, ³ J = 8.3 Hz, 2 H, CH–CH), 5.63–5.78 (m, 1 H, CH), 7.6 (s, 1 H, NH), 9.05 (s, 1 H, NH), 9.17 (s, 1 H, NH).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 42.46 (CH₂), 66.32, 71.02 (CH–CH), 117.49 (CH₂), 133.06 (CH), 158.31 (C=O), 182.78 (C=S).

HRMS (ESI): m/z [M + H]⁺ calcd for C₇H₁₀N₄OS + H: 199.0654; found: 199.0646

1-Benzyl-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one (1l)

Beige powder; yield: 0.27 g (45%) (approach 1), 3.00 g (63%) (approach 2); mp 259–261 °С (MeOH).

IR (KBr): 3350, 3143, 3006, 2871, 1675, 1528, 1484, 1334, 1250, 1122, 1081 cm^–1.

¹H NMR (300 MHz, DMSO-d ₆): δ = 4.01 (d, ² J = 15.5 Hz, 1 Н, CH₂), 4.61 (d, ² J = 15.4 Hz, 1 Н, CH₂), 5.22 (d, ³ J = 8.3 Hz, 1 Н, CH), 5.42 (d, ³ J = 8.3 Hz, 1 Н, CH), 7.27–7.39 (m, 5 H, Ph), 7.72 (s, 1 H, NH), 9.12 (s, 1 H, NH), 9.31 (s, 1 H, NH).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 43.31 (CH₂), 66.33, 70.77 (CH–CH), 127.25, 127.82, 128.49 (CH(Ph)), 137.25 (C(Ph)), 158.48 (C=O), 182.83 (C=S).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₁H₁₂N₄OS + Na: 271.0624; found: 271.0625.

1-(4-Methoxybenzyl)-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one (1m)

Beige powder; yield: 0.32 g (46%) (approach 1), 3.61 g (65%) (approach 2); mp 264–265 °С (MeOH).

IR (KBr): 3348, 3133, 3003, 2871, 1673, 1518, 1483, 1334, 1246, 1178, 1101, 1023 cm^–1.

¹H NMR (300 MHz, DMSO-d ₆): δ = 3.76 (s, 3 H, Me), 3.91 (d, ² J = 15.1 Hz, 1 Н, CH₂), 4.56 (d, ² J = 15.1 Hz, 1 Н, CH₂), 5.17 (d, ³ J = 8.4 Hz, 1 Н, CH), 5.39 (d, ³ J = 8.4 Hz, 1 Н, CH), 6.91 (d, ³ J = 8.5 Hz, 2 Н, CH(PMB)), 7.23 (d, ³ J = 8.5 Hz, 2 Н, CH(PMB)), 7.07 (s, 1 H, NH), 9.10 (s, 1 H, NH), 9.31 (s, 1 H, NH).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 42.70 (CH₂), 55.11 (OMe), 66.30, 70.55 (CH–CH), 113.95, 129.40, 128.49 (CH(PMB)), 119.04 (C(PMB)), 158.44, 158.62 (C=O+C-OMe), 182.83 (C=S).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₄N₄O₂S + H: 279.0910; found: 279.0912.

1-Phenethyl-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one (1n)

Beige powder; yield: 3.20 g (61%) (approach 2); mp 259–260 °С (MeOH).

IR (KBr): 3331, 3164, 1677, 1527, 1487, 1340, 1252, 1024, 1123, 1096, 885, 751, 702, 580 cm^–1.

¹H NMR (300 MHz, DMSO-d ₆): δ = 2.69–2.90 (m, 2 Н, CH₂), 3.19–3.48 (m, 2 Н, CH₂), 5.38 (d, ³ J = 8.4 Hz, 1 Н, CH), 5.47 (d, ³ J = 8.3 Hz, 1 Н, CH), 7.18–7.33 (m, 5 H, Ph), 7.44 (s, 1 H, NH), 8.92 (s, 1 H, NH), 9.20 (s, 1 H, NH).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 23.38, 41.96 (CH₂), 66.36, 71.55 (CH–CH), 126.19, 128.36, 128.71 (CH(Ph)), 139.03 (C(Ph)), 158.52 (C=O), 182.70 (C=S).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₂H₁₄N₄OS + Na: 285.0781; found: 285.0777.

1-Phenyl-5-thioxohexahydroimidazo[4,5-d]imidazol-2(1H)-one (1o)

Violet powder; yield: 0.20 g (34%) (approach 1); mp >300 °С (MeOH).

IR (KBr): 3345, 3177, 1689, 1529, 1503, 1422, 1328, 1266, 1142, 1102, 887, 748, 691 cm^–1.

¹H NMR (300 MHz, DMSO-d ₆): δ = 5.54 (d, ³ J = 8.4 Hz, 1 H, CH), 6.09 (d, ³ J = 8.5 Hz, 1 H, CH), 7.08 (t, ³ J = 7.3 Hz, 1 H, Ph), 7.33 (t, ³ J = 7.8 Hz, 2 H, Ph), 7.56 (d, ³ J = 8.1 Hz, 2 H, Ph), 8.18 (s, 1 H, NH), 9.29 (d, 1 H, NH), 9.42 (s, 1 H, NH).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 65.77, 71.79 (CH–CH), 119.10, 123.06, 128.63 (CH(Ph)), 138.01 (C(Ph)), 156.35 (C=O), 183.47 (C=S).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₀H₁₀N₄OS + Na: 257.0468; found: 257.0465.

4-[2-Oxo-5-thioxohexahydroimidazo[4,5-d]imidazol-1(2H)-yl]-butanoic Acid (1p)

Beige powder; yield: 0.22 g (36%) (approach 1); mp 215–216 °С (H₂O).

IR (KBr): 3405, 3331, 3181, 1715, 1651, 1500, 1337, 1243, 1205, 1129, 1083, 933, 887, 812 cm^–1.

¹H NMR (300 MHz, DMSO-d ₆): δ = 1.60–1.80 (m, 2 Н, CH₂), 2.16 (t, ³ J = 7.5 Hz, 2 Н, CH₂), 3.00 (dt, ² J = 13.9 Hz, ³ J = 6.8 Hz, 1 Н, CH₂), 3.19 (dt, ² J = 14.0 Hz, ³ J = 7.6 Hz, 1 Н, CH₂), 5.37 (d, ³ J = 8.4 Hz, 1 Н, CH), 5.44 (d, ³ J = 8.4 Hz, 1 Н, CH), 7.53 (s, 1 H, NH), 9.04 (s, 1 H, NH), 9.14 (s, 1 H, NH), 11.81–12.32 (br s, 1 H, COOH).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 22.64, 31.01, 39.78 (CH₂), 66.34, 71.44 (CH–CH), 158.72 (C=O), 174.05 (COOH), 182.74 (C=S).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₈H₁₂N₄O₂S + Na: 267.0522; found: 267.0524.

1-(4-Methoxybenzyl)urea (2m)

Urea (200 mmol, 12.00 g) was dissolved in H₂O (50 mL); then, (4-methoxyphenyl)methanamine (5.2 mL, 40 mmol) and 35% aq HCl (2.5 mL) were added. The reaction mixture was refluxed for 4 h and then cooled to r.t. The resulting precipitate was collected by filtration, washed with H₂O (50 mL), and dried in air.

White crystalline plates; yield: 3.82 g (53%); mp 159–160 °С (H₂O) (158–159 °С[42]).

Ureas 2d,g

The corresponding amine (38 mmol) was dissolved in H₂O (40 mL), and then 35% aq HCl (2.1 mL) was added dropwise. The reaction mixture was heated to reflux, and then KOCN (40 mmol, 3.24 g) was added portionwise. The reaction mixture was refluxed for 30 min and then cooled to r.t. The resulting precipitate was collected by filtration and recrystallized from EtOH.

1-Propylurea (2d)

White powder; yield: 3.45 g (89%); mp 109–110 °С (173–174 °C[43]).

1-(Cyclopropylmethyl)urea (2g)

Beige powder; yield: 3.81 g (88%); mp 122–124 °С (MeOH).

IR (KBr): 3416, 3217, 1657, 1605, 1547, 1359, 1310, 1145, 559 cm^–1.

¹H NMR (300 MHz, DMSO-d ₆): δ = 0.03–0.15 (m, 2 H, CH₂), 0.29–0.42 (m, 2 H, CH₂), 0,76–0.92 (m, 1 H, CH), 2.83 (t, ³ J = 6.1 Hz, 2 H, CH₂), 5.39 (s, 2 H, NH₂), 5.97 (s, 1 H, NH).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 2.97 (CH₂), 11.47 (CH), 43.50 (CH₂), 158.71 (C=O).

HRMS (ESI): m/z [M + H]⁺ calcd for C₅H₁₀N₂O + H: 115.0871; found: 115.0863

(8S*,8aS*)-8-Methoxytetrahydro-2H-imidazo[5,1-b][1,3]oxazine-6(7H)-one (6)

A mixture of 2i (0.24 g, 20 mmol), glyoxal hydrate trimer (1.61 g, 7.7 mmol), and H₂O (10 mL) was heated to 50–55 °C. Then NaOH (H₂O) was added dropwise until pH 10 was achieved by the reaction mixture, which was then stirred for 3 h. MeOH (20 mL), NaSCN (3.65 g, 45 mmol), and 35% aq HCl (4.4 mL) were added to the reaction mixture. The precipitate was removed by filtration and washed with MeOH (5 mL). The filtrate was refluxed for 30 min. Then the reaction mixture was cooled to r.t. The reaction mixture was evaporated to dryness, then acetone (5 mL) was added, and the resulting precipitate of compound 6 was collected by filtration and air-dried.

White powder; yield: 0.31 g (9%); mp 164–166 °С (acetone).

IR (KBr): 3207, 3114, 2920, 1707, 1478, 1434, 1353, 1253, 1080, 953, 780, 679 cm^–1.

¹H NMR (300 MHz, DMSO-d ₆): δ = 1.31–1.41 (m, 1 Н, CH₂), 1.44–1.62 (m, 1 Н, CH₂), 2.96–3.10 (m, 1 Н, CH₂), 3.20 (s, 3 Н, Me), 3.64–3.77 (m, 2 Н, CH₂), 3.89–3.98 (m, 1 Н, CH₂), 4.44 (s, 1 Н, CH), 4.79 (s, 1 Н, CH), 8.02 (s, 1 H, NH).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 24.62, 37.48, 65.26 (CH₂), 53.38 (Me), 85.67, 87.58 (CH–CH), 159.03 (C=O).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₇H₁₂N₂O₃ + Na: 195.0740; found: 195.0737.

X-ray Diffraction

X-ray diffraction data for 1a,b,d,j were collected at 120 K on a Bruker APEX2 DUO CCD diffractometer, using graphite monochromated Mo-Kα radiation (λ = 0.71073 Å). Using Olex2,[44] the structures were solved with the ShelXT[45] structure solution program using intrinsic phasing and refined against F ² in the anisotropic-isotropic approximation with the olex2.refine[46] refinement package using least-squares minimization. The hydrogen atoms of NH and OH groups were found in the difference Fourier synthesis, the positions of other hydrogen atoms were calculated, and they all were refined in the isotropic approximation within the riding model. Crystal data and structure refinement parameters are given in Table S1 (SI). CCDC 1992118, 1992119, 1992120, and 1992121 (1a, 1b, 1d, and 1j, respectively) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.

Acknowledgment

X-ray diffraction data were collected using the equipment of the Center for Molecular Composition Studies of the A. N. Nesmeyanov Institute of Organoelement Compounds of the Russian Academy of Sciences (INEOS RAS).

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