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Article

Amination of 5-Spiro-Substituted 3-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones

by
Ekaterina E. Khramtsova
*,
Ekaterina A. Lystsova
,
Evgeniya V. Khokhlova
,
Maksim V. Dmitriev
and
Andrey N. Maslivets
Department of Chemistry, Perm State University, ul. Bukireva 15, 614990 Perm, Russia
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(23), 7179; https://doi.org/10.3390/molecules26237179
Submission received: 15 November 2021 / Revised: 24 November 2021 / Accepted: 25 November 2021 / Published: 26 November 2021
(This article belongs to the Special Issue Modern Trends in Heterocyclic Chemistry)
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Abstract

:
The 3-hydroxy-1,5-dihydro-2H-pyrrol-2-one motif is a valuable scaffold in drug discovery. The replacement of the 3-oxy fragment in 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones-based compounds with a 3-amino one (3-amino analogs of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones, 3-amino-1,5-dihydro-2H-pyrrol-2-ones) can play a crucial role in their biological effect. Thus, approaches to 3-amino-1,5-dihydro-2H-pyrrol-2-ones are of significant interest. We developed an approach to 5-spiro-substituted 3-amino-1,5-dihydro-2H-pyrrol-2-ones that could not be obtained using previously reported approaches (reactions of 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones with amines). The developed approach is based on the thermal decomposition of 1,3-disubstituted urea derivatives of 5-spiro-substituted 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones, which were prepared via their reaction with carbodiimides.

Graphical Abstract

1. Introduction

The 3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (HDP) motif (Figure 1) is a valuable scaffold in drug discovery. Inhibitors of p53–MDM2 protein–protein interaction [1,2], inhibitors of HIV integrase [3,4], antibacterial agents against methicillin-resistant Staphylococcus aureus [5], dengue virus helicase inhibitors [6], P2X3 receptor antagonists [7], and other potential pharmaceuticals [8,9] have been developed on its basis.
The replacement of the 3-oxy fragment in HDP-based compounds with a 3-amino one (3-amino analogs of HDPs, 3-amino-1,5-dihydro-2H-pyrrol-2-ones (ADPs)) can play a crucial role in their biological effect (Figure 1) [1,2,9]. Thus, to investigate a wider chemical space around the HDP scaffold, new approaches to ADPs are of significant interest.
There are three universal strategies towards ADPs enabling their synthesis with a wide range of substituents (Scheme 1). These strategies are the substitution of hydroxyl groups in the corresponding HDPs via their reactions with amines (pathway a) [1,2,7,9,10,11,12], the multicomponent reactions of amines and aldehydes with pyruvic acid derivatives (pathway b) [13,14] or acetylenedicarboxylates (pathway c) [15,16] (Scheme 1).
As a part of our long-standing interest in the synthesis of spiro compounds bearing the HDP moiety [17], we wanted to prepare their 3-amino analogs. However, we were unable to synthesize the desired compounds from HDPs and amines [1,2,7,9,10,11,12], and therefore, herein, we report an alternative approach to ADPs (Scheme 2).

2. Results and Discussion

Initially, we prepared HDPs bearing a rigid spiro substituent at the C5 position, compounds 1a–g, by the reaction of compounds 2a–g with dicyclohexylurea (Scheme 3) [17,18,19]. This reaction proceeded smoothly and yielded target compounds 1a–g in excellent yields (isolated yields of 86–98%). The spectral data of compounds 1a–g were in good agreement with other similar spiro HDPs reported by our group earlier [18,19]. Compounds 1a–g were isolated by simple filtration from the reaction mixture and were sufficiently pure to be used in further experiments without additional purification.
Then, we performed a series of reactions of compound 1a with cyclohexylamine (Table 1) in order to obtain the required cyclohexylamino derivative 3a. The examined conditions (Table 1) were selected according to the previously reported substitution reactions of hydroxyl groups in various non-spiro HDPs (bearing hydrogen and a substituent at the C5 position) with amines [1,2,7,9,10,11,12]. Although the examined conditions were productive in the reported cases [1,2,7,9,10,11,12], in our study, none of them led to the desired results (Table 1). We observed that the reaction mixtures contained unconverted compound 1a (93–99%), cyclohexylamine and small quantities of unidentified side products. The target compound 3a was only observed in trace amounts when 1,4-dioxane was used as the solvent (Table 1, Entries 10,11).
We suppose that such inaction of compound 1a in the reaction with cyclohexylamine could be explained by the fact that the desired transformation proceeded via the participation of the corresponding HDP A in keto form, which underwent a condensation reaction with amine to afford the target 3-amino derivative of HDP B (Scheme 4) [12]. Compound 1a (Scheme 4, structure A, R2 + R3 = spiro) had less conformational flexibility and less propensity for tautomerization to its keto form due to the influence of the rigid spiro-substituent at the C5 position of the pyrrol-2-one moiety than the previously reported [1,2,7,9,10,11,12] non-spiro HDPs bearing hydrogen and a substituent at the C5 position (Scheme 4, structure A, R2 = H, R3 = Alk, Ar, H).
Therefore, we decided to develop a new strategy based on the ability of urea and alkyl/arylureas to decompose with the formation of ammonia/amines and isocyanates (Scheme 5) [20,21].
For the implementation of our strategy, we obtained compounds 4a,b, 1,3-dialkylurea derivatives of compound 1a, via the reaction of compound 1a with inexpensive and commercially available dialkylcarbodiimides 5a,b (Scheme 6). The reaction with dicyclohexylcarbodiimide (DCC) 5a proceeded smoothly at a reagent ratio of 1:1 to give the target compound 4a in an excellent yield (93%). However, the reaction with diisopropylcarbodiimide (DIC) 5b at a reagent ratio of 1:1 yielded the target compound 4b in a lower yield (73%). Such a decrease, when changing DCC to DIC, could be because the boiling point of DIC (145–146 °C) [22] is lower than DCC (151–152 °C at 10 mmHg) [22], and DIC partially evaporated from the reaction mixture. Increasing the DIC ratio to two equivalents increased the isolated yield of compound 4b to 88%. Compounds 4a,b were isolated by filtration from the reaction mixture and were sufficiently pure to be used in further experiments without additional purification. Then, the proposed method was successfully implemented to the synthesis of compounds 4c–n (Scheme 6). This approach worked well with various aryl substituents in compounds 1 (Scheme 6). The involvement of aryl and primary alkyl-bearing carbodiimides 5c,d in this reaction was successful too (Scheme 6).
Probably, the formation of compounds 4a–n proceeded through the pathway of acyl transfer in isourea intermediate C (Scheme 7), which is a common concurrent process for the Steglich esterification [23]. It should be emphasized that although compounds 1a–g contain two different hydroxy groups, enolic and phenolic ones, the reaction with carbodiimides 5a–d proceeded exclusively at the enolic hydroxy group, which could be explained by its higher acidity in comparison with the phenolic one, and, consequently, higher reactivity in reactions with carbodiimides [24].
Having synthesized derivatives 4a–n, we investigated the possibility of their thermal decomposition to afford the desired amino derivatives of HDPs, compounds 3a–n (Table 2). We found that compounds 4a–n readily decomposed at their melting point temperatures to afford the desired compounds 3a–n (84–98%). The proposed method was suitable for various aroyl substituents and R’ substituents in a urea moiety of compounds 4a–n (Table 2).
The structures of compounds 3b, 3c, and 4h were proved by single-crystal X-ray analyses (CCDC 2090985 (3b), 2090984 (3c), 2090986 (4h)).
Preliminary antimicrobial assays [25] of compounds 1a–g and 4a,c–h were carried out (detailed data are given in Supporting Materials). Unfortunately, we found that the tested compounds did not show any significant antimicrobial activity (against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Candida albicans, Cryptococcus neoformans var. grubii) in vitro.

3. Materials and Methods

3.1. General Information

1H and 13C NMR spectra (Supplementary Materials) were acquired on a Bruker Avance III 400 HD spectrometer (Bruker BioSpin AG, Fällanden, Switzerland) (at 400 and 100 MHz, respectively) in CDCl3 (stab. with Ag) or DMSO-d6 using the HMDS signal (in 1H NMR) or solvent residual signals (in 13C NMR, 77.00 for CDCl3, 39.51 for DMSO-d6; in 1H NMR, 7.26 for CDCl3, 2.50 for DMSO-d6) as internal standards. IR spectra were recorded on a Perkin–Elmer Spectrum Two spectrometer (PerkinElmer, Waltham, MA, USA) from mulls in mineral oil. Melting points were measured on a Khimlabpribor PTP apparatus (Pribor-T, Saratov, Russia) or a Mettler Toledo MP70 apparatus (Mettler-Toledo GmbH, Greifensee, Switzerland). Elemental analyses were carried out on a Vario MICRO Cube analyzer (Elementar, Langenselbold, Germany). The reaction conditions were optimized using UPLC-UV-MS (Waters ACQUITY UPLC I-Class system (USA); Acquity UPLC BEH C18 column, grain size of 1.7 μm; acetonitrile–water as eluents; flow rate of 0.6 mL/min; ACQUITY UPLC PDA eλ Detector (Thermo Fisher Scientific, Waltham, MA, USA) (wavelength range of 230–780 nm); Xevo TQD mass detector (Agilent, Santa Clara, CA, USA); electrospray ionization (ESI); positive and negative ion detection; ion source temperature of 150 °C; capillary voltage of 3500–4000 V; cone voltage of 20–70 V; vaporizer temperature of 200 °C). The single-crystal X-ray analyses of compounds 3b, 3c, and 4h were performed on an Xcalibur Ruby diffractometer (Agilent Technologies, Cheadle, UK). The empirical absorption correction was introduced by the multi-scan method using SCALE3 ABSPACK algorithm [26]. Using OLEX2 [27], the structures were solved with the SHELXS-97 [28] program and refined by the full-matrix least-squares minimization in the anisotropic approximation for all non-hydrogen atoms with the SHELXL (accessed on 1 March 2018) [29] program. Hydrogen atoms bound to carbon were positioned geometrically and refined using a riding model. The hydrogen atoms of OH and NH groups were refined freely with isotropic displacement parameters. The contribution of the solvent electron density (for compounds 3b and 4h) was removed using the SQUEEZE routine in PLATON [30]. Thin-layer chromatography (TLC) was performed on Merck silica gel 60 F254 plates using EtOAc/toluene, 1:5 v/v, toluene, EtOAc as eluents. Starting compounds 2a–g were obtained according to reported procedures [31] from oxalyl chloride (purchased from commercial vendors) and heterocyclic enamines (obtained according to reported procedures [31] from commercially available reagents). Toluene for procedures involving compounds 2a–g was dried over Na before use. All other solvents and reagents were purchased from commercial vendors and used as received. Procedures involving compounds 2a–g were carried out in oven-dried glassware.

3.2. Synthetic Methods and Analytic Data of Compounds

3.2.1. General Procedure to Compounds 1a–g

A suspension of the corresponding compound 2 (3.1 mmol) and dicyclohexylurea (3.1 mmol) in 20 mL of toluene was refluxed for 2 h (until the disappearance of the dark violet color of compound 2). Then, the resulting white precipitate was filtered off to afford the desired compound 1.
9-Benzoyl-1,3-dicyclohexyl-8-hydroxy-6-(2-hydroxyphenyl)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(1a). Yield: 1.58 g (94%); white solid; mp 285–287 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.90 (s, 1H), 7.75 (m, 2H), 7.62 (m, 1H), 7.51 (m, 2H), 7.24 (m, 1H), 7.00 (m, 1H), 6.91 (m, 1H), 6.81(m, 1H), 3.84 (m, 1H), 3.08 (m, 1H), 2.16–1.96 (m, 2H), 1.87–1.55 (m, 8H), 1.46 (m, 2H), 1.36–1.10 (m, 7H), 0.95 (m, 1H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 188.5, 169.2, 163.1, 155.5, 154.0, 153.9, 137.3, 132.8, 130.0, 128.6 (2C), 128.2 (2C), 126.7, 120.0, 119.0, 116.7, 113.1, 80.6, 52.1, 51.0, 30.0, 29.5, 28.6 (2C), 25.7, 25.2, 25.2, 25.0, 24.8 (2C) ppm. IR (mineral oil): 3354, 3151, 1779, 1723, 1708, 1678 cm−1. Anal. Calcd (%) for C31H33N3O6: C 68.49; H 6.12; N 7.73. Found: C 68.23; H 6.13; N 7.76. MS (ESI+): m/z calcd for C31H33N3O6+H+: 544.24 [M + H+]; found: 544.18.
1,3-Dicyclohexyl-9-(4-ethoxybenzoyl)-8-hydroxy-6-(2-hydroxyphenyl)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(1b). Yield: 1.78 g (98%); white solid; mp 274–276 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.88 (s, 1H), 7.75 (m, 2H), 7.23 (m, 1H), 7.03–6.98 (m, 3H), 6.90 (m, 1H), 6.81 (m, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.84 (m, 1H), 3.05 (m, 1H), 2.15–1.97 (m, 2H),1.83–1.56 (m, 8H), 1.49–1.41 (m, 2H), 1.37–1.24 (m, 5H), 1.21–1.07 (m, 5H), 0.94 (m, 1H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 186.9, 169.2, 163.2, 162.5, 154.1, 153.9, 131.1 (2C), 130.0, 129.6, 128.1, 126.7, 120.1, 118.9, 116.6, 113.9 (2C), 111.9, 80.7, 63.5, 52.1, 51.0, 30.0, 29.5, 28.7 (2C), 28.6, 25.7, 25.2, 25.0, 24.8 (2C), 14.4 ppm. IR (mineral oil): 3386, 3173, 1777, 1727, 1714, 1683 cm−1. Anal. Calcd (%) for C33H37N3O7: C 67.45; H 6.35; N 7.15. Found: C 67.63; H 6.39; N 7.21. MS (ESI+): m/z calcd for C33H37N3O7+H+: 588.27 [M + H+]; found: 588.24.
1,3-Dicyclohexyl-8-hydroxy-6-(2-hydroxyphenyl)-9-(4-methoxybenzoyl)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(1c). Yield: 1.60 g (90%); white solid; mp 274–276 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.88 (s, 1H), 7.77 (m, 2H), 7.24 (m, 1H), 7.05–6.98 (m, 3H), 6.91 (m, 1H), 6.81 (m, 1H), 3.86–3.81 (m, 4H), 3.06 (m, 1H), 2.15–1.97 (m, 2H), 1.83–1.70 (m, 5H), 1.66–1.54 (m, 3H), 1.49–1.41 (m, 2H), 1.35–1.25 (m, 2H), 1.21–1.08 (m, 5H), 0.94 (m, 1H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 186.9, 169.2, 163.2, 154.1, 153.9, 131.1 (2C), 130.0, 129.8, 128.8, 128.1, 126.7, 120.1, 118.9, 116.6, 113.8, 113.5 (2C), 80.7, 55.4, 52.1, 51.0, 30.0, 29.5, 28.7 (2C), 28.6, 25.7, 25.2, 25.0, 24.8 (2C) ppm. IR (mineral oil): 3385, 3159, 1778, 1727, 1716, 1683 cm−1. Anal. Calcd (%) for C32H35N3O7: C 67.00; H 6.15; N 7.33. Found: C 66.78; H 6.50; N 7.36. MS (ESI+): m/z calcd for C32H35N3O7+H+: 574.26 [M + H+]; found: 574.18.
9-Benzoyl-6-(5-chloro-2-hydroxyphenyl)-1,3-dicyclohexyl-8-hydroxy-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(1d). Yield: 1.56 g (87%); white solid; mp 294–296 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.88 (s, 1H), 7.74–7.68 (m, 4H), 7.24 (m, 1H), 6.99 (m, 1H), 6.90 (m, 1H), 6.81 (m, 1H), 3.84 (m, 1H), 3.09 (m, 1H), 2.12–1.98 (m, 2H), 1.84–1.58 (m, 8H), 1.47 (m, 2H), 1.36–1.05 (m, 7H), 0.95 (m, 1H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 188.5, 169.4, 163.3, 155.7, 153.9, 153.4, 137.3, 132.9, 129.9, 128.7 (2C), 128.3 (2C), 126.3, 121.9, 121.2, 118.2, 113.0, 80.6, 52.2, 51.1, 30.1, 29.5, 29.0, 28.7 (2C), 25.7, 25.3, 25.0, 24.9 (2C) ppm. IR (mineral oil): 3340, 3190, 1782, 1726, 1706, 1672 cm−1. Anal. Calcd (%) for C31H32ClN3O6: C 64.41; H 5.58; N 7.27. Found: C 64.67; H 5.72; N 7.24. MS (ESI+): m/z calcd for C31H32ClN3O6+H+: 578.21 [M + H+]; found: 578.15.
1,3-Dicyclohexyl-8-hydroxy-6-(2-hydroxyphenyl)-9-(4-methylbenzoyl)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(1e). Yield: 1.52 g (88%); white solid; mp 291–293 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.90 (s, 1H), 7.66 (m, 2H), 7.32 (m, 2H), 7.24 (m, 1H), 7.00 (m, 1H), 6.90 (m, 1H), 6.81 (m, 1H), 3.84 (m, 1H), 3.07 (m, 1H), 2.39 (s, 3H), 2.15–1.96 (m, 2H), 1.83–1.54 (m, 8H), 1.47 (m, 2H), 1.36–1.10 (m, 7H), 0.94 (m, 1H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 188.1, 169.3, 163.2, 154.1, 153.9, 143.4, 134.7, 130.0 (2C), 128.8 (2C), 128.1, 126.7, 120.1, 119.0, 116.7, 113.4, 80.7, 52.1, 51.0, 30.0, 29.5, 28.7 (2C), 28.6, 25.7, 25.3, 25.2, 25.0, 24.8 (2C), 21.1 ppm. IR (mineral oil): 3382, 3182, 1779, 1727, 1715, 1682 cm−1. Anal. Calcd (%) for C32H35N3O6: C 68.92; H 6.33; N 7.54. Found: C 69.11; H 6.38; N 7.57. MS (ESI+): m/z calcd for C32H35N3O6+H+: 558.26 [M + H+]; found: 558.22.
1,3-Dicyclohexyl-8-hydroxy-6-(2-hydroxyphenyl)-9-(4-nitrobenzoyl)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(1f). Yield: 1.70 g (93%); white solid; mp 279–281 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.91 (s, 1H), 8.31 (m, 2H), 7.96 (m, 2H), 7.24 (m, 1H), 7.00 (m, 1H), 6.91 (m, 1H), 6.81 (m, 1H), 3.84 (m, 1H), 3.12 (m, 1H), 2.16–1.95 (m, 2H), 1.89–1.59 (m, 8H), 1.49 (m, 2H), 1.36–1.10 (m, 7H), 0.95 (m, 1H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 186.5, 169.5, 163.2, 158.8, 153.9, 149.4, 142.9, 129.8 (2C), 128.8, 128.1, 126.7, 123.3 (2C), 120.2, 118.9, 116.6, 111.4, 80.4, 52.0, 51.0, 30.0, 29.5, 28.7 (2C), 25.7, 25.2, 25.2, 24.9 (2C), 24.9 ppm. IR (mineral oil): 3381, 3126, 1782, 1727, 1704, 1673 cm−1. Anal. Calcd (%) for C31H32N4O8: C 63.26; H 5.48; N 9.52. Found: C 63.29; H 5.50; N 9.53. MS (ESI+): m/z calcd for C31H32N4O8+H+: 589.23 [M + H+]; found: 589.19.
9-(4-Chlorobenzoyl)-1,3-dicyclohexyl-8-hydroxy-6-(2-hydroxyphenyl)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(1g). Yield: 1.54 g (86%); white solid; mp 284–286 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.89 (s, 1H), 7.77 (m, 2H), 7.58 (m, 2H), 7.24 (m, 1H), 6.99 (m, 1H), 6.90 (m, 1H), 6.81 (m, 1H), 3.84 (m, 1H), 3.08 (m, 1H), 2.15–1.95 (m, 2H), 1.87–1.58 (m, 8H), 1.47 (m, 2H), 1.35–1.05 (m, 7H), 0.94 (m, 1H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 187.2, 169.2, 163.1, 156.3, 154.0, 153.8, 137.6, 136.1, 130.5 (2C), 130.0, 128.4 (2C), 126.7, 120.0, 118.9, 116.6, 112.6, 80.5, 52.0, 51.0, 30.0, 29.5, 28.7 (2C), 25.7, 25.2, 25.2, 24.9, 24.8 (2C) ppm. IR (mineral oil): 3369, 3135, 1781, 1729, 1709, 1658 cm−1. Anal. Calcd (%) for C31H32ClN3O6: C 64.41; H 5.58; N 7.27. Found: C 64.52; H 5.64; N 7.39. MS (ESI+): m/z calcd for C31H32ClN3O6+H+: 578.21 [M + H+]; found: 587.14.

3.2.2. General Procedure to Compounds 4a–n

A suspension of the corresponding compound 1 (1.8 mmol) and the corresponding carbodiimide 5 (1.8 mmol for 5a,c,d; 3.6 mmol for DIC 5b) in 20 mL of toluene was refluxed for 2 h. Then, the resulting precipitate was filtered off to afford the desired compound 4.
9-Benzoyl-1,3-dicyclohexyl-1-(1,3-dicyclohexyl-6-(2-hydroxyphenyl)-2,4,7-trioxo-1,3,6-triazaspiro[4.4]non-8-en-8-yl)urea(4a). Yield: 1.26 g (93%); white solid; mp 273–275 °C; 1H NMR (400 MHz, CDCl3): δ = 7.85 (m, 2H), 7.62 (m, 1H), 7.47 (m, 2H), 7.19 (m, 1H), 7.01 (m, 2H), 6.88 (m, 1H), 6.73 (br. s, 1H), 4.85 (d, 1H, J = 4.0 Hz), 4.03 (m, 1H), 3.74 (m, 1H), 3.46 (m, 1H), 2.99 (m, 1H), 2.21 (m, 2H), 2.00–1.50 (m, 22H), 1.44–0.97 (m, 16H) ppm; 13C NMR (100 MHz, CDCl3): δ = 189.4, 168.7, 165.8, 154.5, 154.4, 152.7, 142.5, 137.9, 135.8, 134.2, 130.2, 129.0 (2C), 128.7 (2C), 125.6, 121.7, 121.1, 119.4, 82.1, 59.7, 54.6, 52.8, 49.9, 33.3, 33.0, 31.9, 30.4, 30.4, 30.1, 29.1, 29.0, 26.3, 26.1, 26.1, 29.9, 25.8, 25.7, 25.6, 25.3, 25.2, 25.0, 24.9, 24.7 ppm. IR (mineral oil): 3411, 3132, 1781, 1730, 1652 cm−1. Anal. Calcd (%) for C44H55N5O6: C 70.47; H 7.39; N 9.34. Found: C 70.63; H 7.39; N 9.50. MS (ESI+): m/z calcd for C44H55N5O6+H+: 750.42 [M + H+]; found: 750.38.
1-(9-Benzoyl-1,3-dicyclohexyl-6-(2-hydroxyphenyl)-2,4,7-trioxo-1,3,6-triazaspiro[4.4]non-8-en-8-yl)-1,3-diisopropylurea(4b). Yield: 1.06 g (88%); white solid; mp 231–232 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.96 (s, 1H), 7.85 (m, 2H), 7.68 (m, 1H), 7.52 (m, 2H), 7.23 (m, 1H), 6.99 (m, 1H) 6.91 (m, 1H), 6.82 (m, 1H), 5.78 (d, 1H, J = 4.0 Hz), 4.08 (m, 1H), 3.88 (m, 1H), 3.63 (m, 1H), 3.26 (s, 1H), 3.05 (m, 1H), 2.15–2.03 (m, 2H), 1.81–1.57 (m, 7H), 1.46 (m, 1H), 1.36–1.28 (m, 3H), 1.21–1.11 (m, 5H), 1.06–0.85 (m, 13H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 189.6, 168.4, 163.9, 154.2, 153.8, 153.6, 143.0, 136.6, 135.6, 134.1, 129.9, 128.6 (4C), 126.6, 120.5, 118.9, 116.6, 81.3, 52.9, 51.5, 49.7, 42.1, 29.8, 29.6, 28.7, 28.5, 25.6, 25.2, 25.1, 25.0, 24.7, 24.5, 22.4, 22.3, 21.4, 19.8 ppm. IR (mineral oil): 3404, 3171, 1771, 1747, 1711, 1671 cm−1. Anal. Calcd (%) for C38H47N5O6: C 68.14; H 7.07; N 10.46. Found: C 67.97; H 7.26; N 10.22. MS (ESI+): m/z calcd for C38H47N5O6+H+: 670.36 [M + H+]; found: 670.30.
1,3-Dicyclohexyl-1-(1,3-dicyclohexyl-9-(4-ethoxybenzoyl)-6-(2-hydroxyphenyl)-2,4,7-trioxo-1,3,6-triazaspiro[4.4]non-8-en-8-yl)urea(4c). Yield: 1.30 g (91%); white solid; mp 192–194 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.99 (s, 1H), 7.86 (m, 2H), 7.22 (m, 1H), 6.98 (m, 3H), 6.88 (m, 1H), 6.80 (m, 1H) 5.91 (d, 1H, J = 4.0 Hz), 4.20–4.08 (m, 2H), 3.86 (m, 1H), 3.67 (m, 1H), 3.42 (s, 1H), 2.99 (m, 1H), 2.13–2.00 (m, 2H), 1.84–1.45 (m, 18H), 1.38–0.88 (m, 23H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 187.8, 168.3, 164.2, 163.4, 154.3 (2C), 153.6, 142.1, 139.2, 131.5 (2C), 129.9, 128.5, 126.7, 120.7, 118.9, 116.6, 114.3 (2C), 81.4, 63.7, 57.0, 53.0, 51.4, 49.2, 32.6 (2C), 31.3, 30.3, 29.9, 29.6, 28.7, 28.7, 25.6, 25.3, 25.2 (2C), 25.2, 24.9, 24.8, 24.7 (2C), 24.7 (2C), 24.6, 14.33 ppm. IR (mineral oil): 3357, 3175, 1775, 1731, 1716, 1646 cm−1. Anal. Calcd (%) for C46H59N5O7: C 69.58; H 7.49; N 8.82. Found: C 69.71; H 7.45; N 8.89. MS (ESI+): m/z calcd for C46H59N5O7+H+: 794.45 [M + H+]; found: 794.39.
1,3-Dicyclohexyl-1-(1,3-dicyclohexyl-6-(2-hydroxyphenyl)-9-(4-methoxybenzoyl)-2,4,7-trioxo-1,3,6-triazaspiro[4.4]non-8-en-8-yl)urea(4d). Yield: 1.28 g (91%); white solid; mp 230–232 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.96 (s, 1H), 7.88 (m, 2H), 7.22 (m, 1H), 6.98 (m, 3H), 6.89 (m, 1H), 6.81 (m, 1H), 5.87 (d, 1H, J = 8.0 Hz), 3.91–3.84 (m, 4H), 3.67 (m, 1H), 3.43 (m, 1H), 2.99 (m, 1H), 2.11–2.01 (m, 2H), 1.85–1.45 (m, 18H), 1.39–0.86 (m, 20H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 187.8, 168.2, 164.1, 164.0, 154.2 (2C), 153.6, 142.1, 139.1, 131.4 (2C), 129.8, 128.6, 126.6, 120.7, 118.9, 116.5, 113.9 (2C), 81.36, 57.0, 55.6, 53.0, 51.4, 49.2, 32.5 (2C), 32.5, 31.2, 30.2, 29.8, 29.6, 28.7, 28.6, 25.6, 25.3, 25.2 (2C), 25.1, 24.8, 24.7, 24.7, 24.6 (2C), 24.5 ppm. IR (mineral oil): 3341, 3176, 1779, 1732, 1716, 1645 cm−1. Anal. Calcd (%) for C45H57N5O7: C 69.30; H 7.37; N 8.98. Found: C 69.53; H 7.45; N 8.89. MS (ESI+): m/z calcd for C45H57N5O7+H+: 780.43 [M + H+]; found: 780.37.
1-(9-Benzoyl-6-(5-chloro-2-hydroxyphenyl)-1,3-dicyclohexyl-2,4,7-trioxo-1,3,6-triazaspiro[4.4]non-8-en-8-yl)-1,3-dicyclohexylurea(4e). Yield: 1.33 g (94%); white solid; mp 258–260 °C; 1H NMR (400 MHz, DMSO-d6): δ = 10.47 (s, 1H), 7.88 (m, 2H), 7.69 (m, 1H), 7.50 (m, 2H), 7.31 (m, 1H), 7.01 (m, 1H) 6.91 (m, 1H), 6.00 (d, 1H, J = 8.0 Hz), 3.89 (m, 1H), 3.63 (m, 1H), 3.53 (m, 1H), 3.01 (m, 1H), 2.15–2.02 (m, 2H), 1.84–1.45 (m, 18H), 1.37–0.83 (m, 20H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 189.7, 168.3, 164.1, 154.2, 153.6 (2C), 143.1, 137.7, 135.7, 134.5, 129.8, 128.9 (2C), 128.7 (2C), 126.4, 121.9, 121.7, 118.2, 81.3, 57.5, 53.1, 51.6, 49.4, 32.6 (2C), 32.5, 31.3, 30.3, 30.1, 29.7, 29.0, 28.7, 25.7, 25.4 (2C), 25.3 (2C), 25.2, 25.0, 24.9, 24.8 (2C), 24.6 ppm. IR (mineral oil): 3412, 3198, 1782, 1727, 1657 cm−1. Anal. Calcd (%) for C44H54ClN5O6: C 67.37; H 6.94; N 8.93. Found: C 67.43; H 6.88; N 9.02. MS (ESI+): m/z calcd for C44H54ClN5O6+H+: 783.38 [M + H+]; found: 783.32.
1,3-Dicyclohexyl-1-(1,3-dicyclohexyl-6-(2-hydroxyphenyl)-9-(4-methylbenzoyl)-2,4,7-trioxo-1,3,6-triazaspiro[4.4]non-8-en-8-yl)urea(4f). Yield: 1.22 g (89%); white solid; mp 245–253 °C; 1H NMR (400 MHz, DMSO-d6): δ = 10.00 (s, 1H), 7.77 (m, 2H), 7.30 (m, 2H), 7.22 (m, 1H), 6.98 (m, 1H), 6.89 (m, 1H) 6.81 (m, 1H), 5.84 (d, 1H, J = 8.0 Hz), 3.87 (m, 1H), 3.67 (m, 1H), 3.38 (m, 1H), 3.00 (m, 1H), 2.39 (s, 3H), 2.14–2.00 (m, 2H), 1.84–1.45 (m, 18H), 1.41–0.85 (m, 20H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 189.2, 168.3, 164.0, 154.2, 154.1, 153.6, 145.0, 142.7, 138.3, 133.3 (2C), 129.9, 129.2 (2C), 128.9, 126.7, 120.6, 119.0, 116.6, 81.4, 59.6, 57.2, 53.0, 51.4, 49.2, 32.6, 32.5, 31.2, 30.2, 29.9, 29.6, 28.7, 28.6, 25.6, 25.4, 25.2 (2C), 25.2, 25.1, 24.8, 24.8, 24.7, 24.6 (2C), 21.3 ppm. IR (mineral oil): 3336, 3164, 1778, 1734, 1715, 1650 cm−1. Anal. Calcd (%) for C45H57N5O6: C 70.75; H 7.52; N 9.17. Found: C 70.91; H 7.62; N 9.24. MS (ESI+): m/z calcd for C45H57N5O6+H+: 764.44 [M + H+]; found: 764.34.
1,3-Dicyclohexyl-1-(1,3-dicyclohexyl-6-(2-hydroxyphenyl)-9-(4-nitrobenzoyl)-2,4,7-trioxo-1,3,6-triazaspiro[4.4]non-8-en-8-yl)urea(4g). Yield: 1.27 g (89%); white solid; mp 229–231 °C; 1H NMR (400 MHz, DMSO-d6): δ = 10.10 (s, 1H), 8.33 (m, 2H), 8.01 (m, 2H), 7.24 (m, 1H), 6.99 (m, 1H), 6.90 (m, 1H) 6.83 (m, 1H), 5.99 (d, 1H, J = 8.0 Hz), 3.87 (m, 1H), 3.73 (m, 1H), 3.49 (m, 1H), 3.06 (m, 1H), 2.14–1.97 (m, 2H), 1.81–1.41 (m, 22H), 1.36–0.88 (m, 16H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 188.6, 168.4, 163.8, 154.2, 154.1, 153.6, 150.2, 144.9, 140.6, 138.3, 130.2, 129.9 (2C), 126.8, 123.9 (2C), 120.4, 119.1, 116.7, 81.1, 57.8, 52.9, 51.6, 49.5, 32.5, 32.3 (2C), 29.9, 29.8, 28.7, 28.7, 25.7, 25.6, 25.4, 25.3, 25.2 (2C), 25.0, 24.9 (2C), 24.7, 24.7 (2C), 24.6 ppm. IR (mineral oil): 3336, 3194, 1779, 1731, 1716, 1656 cm−1. Anal. Calcd (%) for C44H54N6O8: C 66.48; H 6.85; N 10.57. Found: C 66.35; H 6.89; N 10.44. MS (ESI+): m/z calcd for C44H54N6O8+H+: 794.40 [M + H+]; found: 794.36.
1-(9-(4-Chlorobenzoyl)-1,3-dicyclohexyl-6-(2-hydroxyphenyl)-2,4,7-trioxo-1,3,6-triazaspiro[4.4]non-8-en-8-yl)-1,3-dicyclohexylurea(4h). Yield: 1.31 g (93%); white solid; mp 203–204 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.98 (s, 1H), 7.86 (m, 2H), 7.58 (m, 2H), 7.23 (m, 1H), 6.99 (m, 1H), 6.90 (m, 1H), 6.81 (m, 1H), 5.94 (d, 1H, J = 4.0 Hz), 3.87 (m, 1H), 3.73 (m, 1H), 3.33 (m, 1H), 3.03 (m, 1H), 2.14–1.99 (m, 2H), 1.82–1.40 (m, 20H), 1.34–0.87 (m, 18H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 188.5, 168.3, 163.8, 154.2, 154.0, 153.5, 143.7, 139.0, 134.4, 130.4, 129.9, 128.8 (2C), 126.7, 120.5 (2C), 118.9, 116.6, 81.1, 57.4, 52.9, 51.4, 49.3, 32.5, 32.3 (2C), 31.2, 30.0, 29.8, 29.6, 28.6, 28.6 (2C), 25.6, 25.4, 25.2 (2C), 25.2, 25.1, 25.0, 24.8, 24.6 (2C), 24.6 ppm. IR (mineral oil): 3345, 3181, 1780, 1731, 1718, 1655 cm−1. Anal. Calcd (%) for C44H54ClN5O6: C 67.37; H 6.94; N 8.93. Found: C 67.76; H 7.11; N 9.02. MS (ESI+): m/z calcd for C44H54ClN5O6+H+: 784.38 [M + H+]; found: 784.33. Crystal structure of compound 4h was deposited at the Cambridge Crystallographic Data Centre with the deposition number CCDC 2090986.
1-(1,3-Dicyclohexyl-6-(2-hydroxyphenyl)-9-(4-methylbenzoyl)-2,4,7-trioxo-1,3,6-triazaspiro[4.4]non-8-en-8-yl)-1,3-diisopropylurea(4i). Yield: 1.05 g (85%); yellow solid; mp 158–160 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.96 (s, 1H), 7.76 (m, 2H), 7.32 (m, 2H), 7.23 (m, 1H), 6.99 (m, 1H) 6.90 (m, 1H), 6.82 (m, 1H), 5.73 (d, 1H, J = 8.0 Hz), 4.08 (m, 1H), 3.87 (m, 1H), 3.64 (m, 1H), 3.26 (s, 1H), 3.03 (m, 1H), 2.39 (s, 3H), 2.14–2.03 (m, 2H), 1.85–1.53 (m, 7H), 1.47 (m, 1H), 1.37–1.28 (m, 3H), 1.20–1.11 (m, 5H), 1.04–0.86 (m, 13H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 189.1, 168.4, 164.0, 154.1, 153.8, 153.6, 144.8, 142.5, 139.7, 133.1, 130.0, 129.2 (2C), 128.8 (2C), 126.5, 120.6, 118.9, 116.5, 81.3, 52.9, 51.5, 49.6, 42.1, 29.8, 29.6, 28.7, 28.5, 25.6, 25.2, 25.1, 25.0, 24.7, 24.5, 22.4, 22.3, 21.4, 21.17, 19.8 ppm. IR (mineral oil): 3324, 3180, 1799, 1748, 1693, 1669, 1644 cm−1. Anal. Calcd (%) for C39H49N5O6: C 68.50; H 7.22; N 10.24. Found: C 68.65; H 7.26; N 10.30. MS (ESI+): m/z calcd for C39H49N5O6+H+: 684.38 [M + H+]; found: 684.34.
1-(1,3-Dicyclohexyl-6-(2-hydroxyphenyl)-9-(4-methoxybenzoyl)-2,4,7-trioxo-1,3,6-triazaspiro[4.4]non-8-en-8-yl)-1,3-diisopropylurea(4j). Yield: 1.08 g (86%); white solid; mp 150–152 °C; 1H NMR (400 MHz, CDCl3): δ = 7.86 (m, 2H), 7.18 (m, 1H), 7.01 (m, 3H), 6.94 (m, 2H), 6.86 (m, 1H), 4.88 (d, 1H, J = 8.0 Hz), 4.22 (m, 1H), 4.02 (m, 1H), 3.88 (s, 3H), 3.76 (m, 1H), 2.97 (m, 1H), 2.27–2.14 (m, 2H), 2.01 (m, 1H), 1.92–1.69 (m, 6H), 1.60 (m, 1H), 1.51–1.47 (m, 2H), 1.44–0.88 (m, 20H) ppm; 13C NMR (100 MHz, CDCl3): δ = 187.5, 168.8, 165.8, 164.7, 154.5, 154.4, 152.8, 141.5, 138.6, 131.6 (2C), 130.2, 128.5, 125.8, 121.6, 120.9, 119.1, 114.1 (2C), 82.3, 55.5, 54.6, 52.8, 51.2, 43.1, 30.4, 30.2, 29.2, 28.9, 26.1, 25.9, 25.9 (2C), 25.2, 25.0, 23.0, 22.6, 22.0, 20.2 ppm. IR (mineral oil): 3421, 3198, 1716, 1686, 1664, 1649 cm−1. Anal. Calcd (%) for C39H49N5O7: C 66.93; H 7.06; N 10.01. Found: C 67.02; H 7.00; N 10.05. MS (ESI+): m/z calcd for C39H49N5O7+H+: 700.37 [M + H+]; found: 700.32.
1-(9-(4-Chlorobenzoyl)-1,3-dicyclohexyl-6-(2-hydroxyphenyl)-2,4,7-trioxo-1,3,6-triazaspiro[4.4]non-8-en-8-yl)-1,3-diisopropylurea(4k). Yield: 1.12 g (88%); white solid; mp 154–157 °C; 1H NMR (400 MHz, CDCl3): δ = 7.80 (m, 2H), 7.46 (m, 2H), 7.19 (m, 1H), 6.99 (m, 2H), 6.87 (m, 1H), 4.87 (d, 1H, J = 4.0 Hz), 4.20 (m, 1H), 4.02 (m, 1H), 3.72 (m, 1H), 2.96 (m, 1H), 2.20 (m, 2H), 2.00 (m, 1H), 1.92–1.70 (m, 6H), 1.63–1.62 (m, 1H), 1.51–1.49 (m, 2H), 1.44–1.23 (m, 6H), 1.18–1.00 (m, 14H) ppm; 13C NMR (100 MHz, CDCl3): δ = 188.1, 168.7, 165.4, 154.5, 154.3, 152.8, 142.7, 141.0, 137.2, 134.0, 130.3 (3C), 129.2 (2C), 125.7, 121.3, 121.0, 119.0, 82.1, 54.6, 52.8, 51.3, 43.2, 30.4, 30.3, 29.1, 28.9, 26.1, 25.9, 25.8, 25.2, 25.0, 23.4, 23.0, 22.6, 21.9, 20.2 ppm. IR (mineral oil): 3173, 3083, 1702, 1681, 1666 cm−1. Anal. Calcd (%) for C38H46ClN5O6: C 68.81; H 6.58; N 9.94. Found: C 68.85; H 6.63; N 9.89. MS (ESI+): m/z calcd for C38H46ClN5O6+H+: 704.32 [M + H+]; found: 704.30.
9-Benzoyl-1-(1,3-dicyclohexyl-6-(2-hydroxyphenyl)-2,4,7-trioxo-1,3,6-triazaspiro[4.4]non-8-en-8-yl)-1,3-diphenylurea(4l). Yield: 1.14 g (86%); pale yellow solid; mp 148–150 °C; 1H NMR (400 MHz, CDCl3): δ = 7.69 (m, 2H), 7.55 (m, 1H), 7.39 (m, 2H), 7.27–7.17 (m, 4H), 7.16–7.03 (m, 7H), 6.88 (m, 2H), 6.80–6.67 (m, 3H), 3.97 (m, 1H), 3.12 (m, 1H), 2.14 (m, 2H), 2.96–0.95 (m, 18H) ppm; 13C NMR (100 MHz, CDCl3): δ = 188.1, 168.1, 164.5, 154.4, 152.7, 152.3, 144.2, 140.4, 137.1, 136.6, 134.4, 134.1, 130.3, 129.9 (2C), 129.0 (2C), 128.9, 128.7 (2C), 127.0, 125.8, 125.1 (2C), 124.5, 121.9, 121.8, 121.2, 120.0 (2C), 119.8, 82.0, 54.4, 52.7, 30.5, 30.2, 29.0 (2C), 26.1, 26.0, 25.8, 25.7, 25.1, 25.1 ppm. IR (mineral oil): 3169, 1778, 1721, 1647 cm−1. Anal. Calcd (%) for C44H43N5O6: C 71.62; H 5.87; N 9.49. Found: C 71.89; H 5.91; N 9.55. MS (ESI+): m/z calcd for C44H43N5O6+H+: 738.33 [M + H+]; found: 738.26.
1-(1,3-Dicyclohexyl-6-(2-hydroxyphenyl)-2,4,7-trioxo-1,3,6-triazaspiro[4.4]non-8-en-8-yl)-9-(4-ethoxybenzoyl)-1,3-diphenylurea(4m). Yield: 1.21 g (86%); yellow solid; mp 161–163 °C; 1H NMR (400 MHz, CDCl3): δ = 7.72 (m, 2H), 7.32–7.05 (m, 11H), 6.94–6.85 (m, 3H), 6.78 (m, 2H), 6.71 (m, 1H), 4.09 (q, J = 6.8 Hz, 2H), 3.98 (m, 1H), 3.10 (m, 1H), 2.16 (m, 2H), 1.91–0.99 (m, 21H) ppm; 13C NMR (100 MHz, CDCl3): δ = 186.2, 168.1, 164.6, 164.1, 154.4, 152.6, 152.3, 143.4, 140.4, 137.2, 135.8, 131.4 (2C), 130.2, 129.8 (2C), 129.3, 129.0 (2C), 127.1, 125.7, 125.3 (2C), 124.4, 122.0, 121.3, 120.0 (3C), 114.5 (2C), 82.0, 64.0, 54.5, 52.7, 30.5, 30.2, 29.0 (2C), 26.1, 25.9, 25.8 (2C), 25.1 (2C), 14.5 ppm. IR (mineral oil): 3327, 3183, 1778, 1721, 1644 cm−1. Anal. Calcd (%) for C46H47N5O7: C 70.66; H 6.06; N 8.96. Found: C 70.34; H 6.14; N 9.05. MS (ESI+): m/z calcd for C46H47N5O7+H+: 782.36 [M + H+]; found: 782.36.
1,3-Dibutyl-1-(1,3-dicyclohexyl-6-(2-hydroxyphenyl)-2,4,7-trioxo-1,3,6-triazaspiro[4.4]non-8-en-8-yl)-9-(4-ethoxybenzoyl)urea(4n). To precipitate compound 4n, hexane (50 mL) was added to the reaction mixture. Yield: 1.19 g (89%); pale yellow solid; mp 138–140 °C; 1H NMR (400 MHz, CDCl3): δ = 7.71 (m, 2H), 7.20 (m, 1H), 7.03–6.85 (m, 5H), 5.05 (m, 1H), 4.11 (q, J = 6.8 Hz, 2H), 4.05–3.97 (m, 1H), 3.71–3.64 (m, 1H), 3.51–3.44 (m, 1H), 3.05–2.97 (m, 1H), 2.95–2.84 (m, 2H), 2.19 (m, 2H), 2.05–0.87 (m, 35H) ppm; 13C NMR (100 MHz, CDCl3): δ = 187.0, 169.0, 165.4, 164.1, 155.1, 154.4, 152.6, 142.6, 132.4, 131.0 (2C), 130.3, 128.0, 125.5, 121.8, 121.2, 119.5, 114.7 (2C), 82.1, 63.9, 54.6, 52.8, 48.7, 40.7, 31.4 (2C), 31.3, 30.4, 30.1, 29.1, 28.9, 26.1, 25.9, 25.8, 25.2, 25.0, 20.1, 20.0, 14.6, 13.8 (2C) ppm. IR (mineral oil): 3538, 3271, 1780, 1724, 1642 cm−1. Anal. Calcd (%) for C42H55N5O7: C 67.99; H 7.47; N 9.44. Found: C 67.64; H 7.53; N 9.31. MS (ESI+): m/z calcd for C42H55N5O7+H+: 742.42 [M + H+]; found: 742.37.

3.2.3. General Procedure to Compounds 3a–n

The corresponding compound 4 (0.5 mmol) was put into an oven-dried tube, pressed slightly, and then, it was heated at 160–290 °C (the temperature for each compound is given in Table 2; caution: R′NCO evolves during the reaction). The reaction mixture was cooled to room temperature and scrubbed with hexane (about 10 mL) to give the appropriate compound 3.
9-Benzoyl-1,3-dicyclohexyl-8-(cyclohexylamino)-6-(2-hydroxyphenyl)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(3a). Yield: 300 mg (96%); white solid; mp 215–217 °C; 1H NMR (400 MHz, CDCl3): δ = 7.69 (m, 2H), 7.59 (m, 1H), 7.51 (m, 2H), 7.24 (m, 1H), 7.08 (m, 1H), 7.03 (m, 1H), 6.91 (m, 1H), 6.45 (br. s, 1H), 5.60 (d, 1H, J = 8.0 Hz), 3.99 (m, 1H), 2.84 (m, 1H), 2.22–2.10 (m, 2H), 1.97–1.82 (m, 6H), 1.68–1.53 (m, 7H), 1.45–0.75 (m, 16H) ppm; 13C NMR (100 MHz, CDCl3): δ = 189.7, 170.3, 165.7, 154.7, 152.4, 139.9, 132.7, 130.4, 129.0 (2C), 128.1, 126.1, 122.1, 121.5 (2C), 120.0, 107.1, 83.1, 53.8, 52.3, 33.9, 32.9, 32.4, 30.5, 30.0, 29.1, 29.0, 26.4, 26.0, 25.9, 25.9, 25.2, 25.2, 25.1, 24.5, 24.2 ppm. IR (mineral oil): 3363, 3276, 1767, 1724, 1700 cm−1. Anal. Calcd (%) for C37H44N4O5: C 71.13; H 7.10; N 8.97. Found: C 71.20; H 7.17; N 8.93. MS (ESI+): m/z calcd for C37H44N4O5+H+: 625.34 [M + H+]; found: 625.31.
9-Benzoyl-1,3-dicyclohexyl-6-(2-hydroxyphenyl)-8-(isopropylamino)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(3b). Yield: 263 mg (90%); white solid; mp 147–149 °C; 1H NMR (400 MHz, CDCl3): δ = 7.70 (m, 2H), 7.58 (m, 1H), 7.49 (m, 2H), 7.23 (m, 1H), 7.05 (m, 2H), 6.90 (m, 1H), 6.49 (m, 1H), 5.49 (d, 1H, J = 8.0 Hz), 3.98 (m, 1H), 3.29 (m, 1H), 2.84 (m, 1H), 2.22–2.09 (m, 2H), 1.97–1.76 (m, 5H), 1.74–1.66 (m, 3H), 1.58–1.51 (m, 2H), 1.39–1.04 (m, 8H), 0.99–0.94 (m, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ = 189.6, 170.2, 165.6, 154.6, 152.4, 139.6, 132.8, 130.4, 129.0 (2C), 128.0 (2C), 126.0, 122.0, 121.5, 119.9, 107.7, 83.0, 53.8, 52.3, 46.9, 30.5, 30.0, 29.0, 29.0, 26.4, 26.0, 25.9, 25.8, 25.2, 25.2, 22.7, 22.4 ppm. IR (mineral oil): 3354, 3262, 3170, 1726 cm−1. Anal. Calcd (%) for C34H40N4O5: C 69.84; H 6.90; N 9.58. Found: C 69.93; H 6.84; N 9.61. MS (ESI+): m/z calcd for C34H40N4O5+H+: 585.31 [M + H+]; found: 585.30. Crystal structure of compound 3b was deposited at the Cambridge Crystallographic Data Centre with the deposition number CCDC 2090985.
1,3-Dicyclohexyl-8-(cyclohexylamino)-9-(4-ethoxybenzoyl)-6-(2-hydroxyphenyl)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(3c). Yield: 311 mg (93%); white solid; mp 152–154 °C; 1H NMR (400 MHz, CDCl3): δ = 7.70 (m, 2H), 7.23 (m, 1H), 7.07 (m, 1H), 7.02 (m, 1H), 6.97 (m, 2H), 6.90 (m, 1H), 6.45 (s, 1H), 5.46 (br. s, 1H), 4.17–4.09 (m, 2H), 4.00 (m, 1H), 2.81 (m, 1H), 2.24–2.12 (m, 2H), 1.93–1.80 (m, 7H), 1.68–1.44 (m, 11H), 1.38–0.76 (m, 14H) ppm; 13C NMR (100 MHz, CDCl3): δ = 188.6, 170.4, 166.0, 163.0, 154.7, 141.6, 132.2, 130.5 (2C), 130.3, 125.9, 122.2, 121.5 (2C), 120.0, 114.7, 107.8, 83.2, 63.9, 53.8, 52.3, 33.1, 32.4, 30.5, 30.0, 29.1, 29.0, 26.4, 26.0, 25.9, 25.9, 25.2, 25.2, 25.2 (2C), 24.6, 24.3, 14.6 ppm. IR (mineral oil): 3196, 1760, 1718, 1687, 1662 cm−1. Anal. Calcd (%) for C39H48N4O6: C 70.04; H 7.23; N 8.38. Found: C 70.16; H 7.20; N 8.44. MS (ESI+): m/z calcd for C39H48N4O6+H+: 669.37 [M + H+]; found: 669.32. Crystal structure of compounds 3c was deposited at the Cambridge Crystallographic Data Centre with the deposition number CCDC 2090984.
1,3-Dicyclohexyl-8-(cyclohexylamino)-6-(2-hydroxyphenyl)-9-(4-methoxybenzoyl)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(3d). Yield: 291 mg (91%); white solid; mp 275–277 °C; 1H NMR (400 MHz, CDCl3): δ = 7.71 (m, 2H), 7.23 (m, 1H), 7.08–6.97 (m, 4H), 6.90 (m, 1H), 6.46 (br. s, 1H), 5.48 (d, 1H, J = 12.0 Hz), 4.00 (m, 1H), 3.89 (s, 3H), 2.81 (m, 1H), 2.18 (m, 2H), 1.91–1.82 (m, 7H), 1.68–1.43 (m, 7H), 1.37–0.75 (m, 15H) ppm; 13C NMR (100 MHz, CDCl3): δ = 188.5, 170.4, 166.0, 163.6, 154.7, 152.3, 132.4, 130.5 (2C), 130.3, 125.9, 122.2, 121.5, 120.0, 114.2 (2C), 107.7, 83.0, 55.6, 53.8, 53.7, 52.3, 33.1, 32.4, 30.5, 30.0, 29.1, 29.0, 26.4, 26.0, 25.9, 25.9, 25.2, 25.2, 25.1, 24.6, 24.3 ppm. IR (mineral oil): 3376, 3282, 1764, 1723, 1700 cm−1. Anal. Calcd (%) for C38H46N4O5: C 69.70; H 7.08; N 8.56. Found: C 69.79; H 7.03; N 8.61. MS (ESI+): m/z calcd for C38H46N4O5+H+: 639.35 [M + H+]; found: 639.30.
9-Benzoyl-6-(5-chloro-2-hydroxyphenyl)-1,3-dicyclohexyl-8-(cyclohexylamino)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(3e). Yield: 297 mg (90%); white solid; mp 240–242 °C; 1H NMR (400 MHz, DMSO-d6): δ = 10.23 (s, 1H), 7.66 (m, 3H), 7.57 (m, 2H), 7.30 (m, 1H), 7.00 (m, 1H), 6.90 (m, 1H), 3.85 (m, 1H), 3.01 (m, 1H), 2.16–2.02 (m, 2H), 1.84–1.72 (m, 5H), 1.66–1.13 (m, 17H), 1.07–0.83 (m, 6H), 0.69 (m, 1H), 0.35 (m, 1H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 189.6, 170.1, 163.5, 153.9, 153.2, 142.9, 139.8, 132.7, 129.7, 128.9 (2C), 127.9, 125.8, 121.8 (2C), 121.5, 118.2, 104.4, 82.3, 54.4, 51.9, 50.9, 31.4, 30.8, 30.2, 29.4, 28.9, 28.7, 25.7, 25.2, 25.1, 24.9, 24.8 (2C), 24.4, 24.3, 24.2 ppm. IR (mineral oil): 3362, 3280, 1767, 1723, 1700 cm−1. Anal. Calcd (%) for C37H43ClN4O5: C 67.41; H 6.58; N 8.50. Found: C 67.53; H 6.62; N 8.54. MS (ESI+): m/z calcd for C37H43ClN4O5+H+: 659.30 [M + H+]; found: 659.31.
1,3-Dicyclohexyl-8-(cyclohexylamino)-6-(2-hydroxyphenyl)-9-(4-methylbenzoyl)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(3f). Yield: 313 mg (98%); white solid; mp 159–190 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.82 (s, 1H), 7.58 (m, 2H), 7.38 (m, 2H), 7.22 (m, 1H), 6.98 (m, 1H), 6.88 (m, 1H), 6.80 (m, 1H), 6.76 (m, 1H), 3.83 (m, 1H), 3.01 (m, 1H), 2.39 (s, 3H), 2.15–1.97 (m, 2H), 1.83–1.72 (m, 5H), 1.66–1.41 (m, 7H), 1.35–0.99 (m, 13H), 0.96–0.84 (m, 2H), 0.68 (m, 1H), 0.39 (m, 1H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 189.4, 170.2, 163.6, 154.0 (2C), 143.0 (2C), 137.4, 129.8, 129.3 (2C), 127.9 (2C), 126.2, 120.5, 118.8, 116.6, 104.6, 82.4, 54.1, 51.9, 50.8, 31.4, 31.1, 30.0, 29.4, 28.7 (2C), 25.7, 25.3, 25.2, 25.1, 24.8 (2C), 24.5, 24.3, 24.2, 21.0 ppm. IR (mineral oil): 3354, 3277, 1787, 1724, 1700 cm−1. Anal. Calcd (%) for C38H46N4O5: C 71.45; H 7.26; N 8.77. Found: C 71.37; H 7.23; N 8.85. MS (ESI+): m/z calcd for C38H46N4O5+H+: 639.35 [M + H+]; found: 639.30.
1,3-Dicyclohexyl-8-(cyclohexylamino)-6-(2-hydroxyphenyl)-9-(4-nitrobenzoyl)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(3g). Yield: 301 mg (90%); white solid; mp 164–166 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.89 (s, 1H), 8.40 (m, 2H), 7.86 (m, 2H), 7.32 (m, 1H), 7.24 (m, 1H), 6.99 (m, 1H), 6.88 (m, 1H), 6.81 (m, 1H), 3.83 (m, 1H), 3.04 (m, 1H), 2.16–1.95 (m, 2H), 1.81–1.70 (m, 5H), 1.65–1.09 (m, 19H), 1.01–0.74 (m, 4H), 0.34 (br. s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 187.5, 170.1, 163.0, 154.0, 153.9, 149.5, 144.7, 144.3, 130.0, 129.4 (2C), 126.2, 124.2 (2C), 120.3, 118.9, 116.7, 82.2, 55.6, 51.84, 50.89, 31.53, 30.1, 29.5, 28.7 (2C), 25.8, 25.3, 25.2, 24.9, 24.9, 24.8, 24.4 (2C), 24.4, 24.3 ppm. IR (mineral oil): 3313, 3270, 1782, 1727, 1700 cm−1. Anal. Calcd (%) for C37H43N5O7: C 66.35; H 6.47; N 10.46. Found: C 66.44; H 6.53; N 10.58. MS (ESI+): m/z calcd for C37H43N5O7+H+: 670.32 [M + H+]; found: 670.25.
9-(4-Chlorobenzoyl)-1,3-dicyclohexyl-8-(cyclohexylamino)-6-(2-hydroxyphenyl)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(3h). Yield: 297 mg (90%); white solid; mp 173–175 °C; 1H NMR (400 MHz, CDCl3): δ = 7.65 (m, 2H), 7.49 (m, 2H), 7.24 (m, 1H), 7.04 (m, 2H), 6.92 (m, 1H), 6.38 (s, 1H), 5.77 (br. s, 1H), 3.97 (m, 1H), 2.81 (m, 1H), 2.21–2.09 (m, 2H), 1.95–1.80 (m, 7H), 1.68–1.46 (m, 9H), 1.36–0.85 (m, 13H) ppm; 13C NMR (100 MHz, CDCl3): δ = 188.4, 170.1, 165.5, 154.6, 152.3, 139.2, 138.1, 130.5, 129.5 (2C), 129.3 (2C), 126.0, 122.0, 121.6, 120.0, 106.8, 83.1, 53.8, 52.3, 32.9, 32.4, 32.4, 30.5, 30.1, 29.1, 29.0, 26.4, 26.0, 25.9, 25.9, 25.2, 25.2, 25.1, 24.5, 24.3 ppm. IR (mineral oil): 3379, 3278, 1767, 1724, 1701, 1633 cm−1. Anal. Calcd (%) for C37H43ClN4O5: C 67.41; H 6.58; N 8.50. Found: C 67.53; H 6.61; N 8.47. MS (ESI+): m/z calcd for C37H43ClN4O5+H+: 659.30 [M + H+]; found: 659.24.
1,3-Dicyclohexyl-6-(2-hydroxyphenyl)-8-(isopropylamino)-9-(4-methylbenzoyl)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(3i). Yield: 281 mg (94%); white solid; mp 146–148 °C; 1H NMR (400 MHz, CDCl3): δ = 7.62 (m, 2H), 7.28 (m, 1H), 7.21 (m, 1H), 7.07 (m, 1H), 7.00 (m, 1H), 6.89 (m, 1H), 6.58 (br. s, 1H), 5.43 (d, 1H, J = 12.0 Hz), 3.98 (m, 1H), 3.30 (m, 1H), 2.83 (m, 1H), 2.43 (s, 3H), 2.22–2.10 (m, 2H), 1.95–1.65 (m, 8H), 1.56–1.50 (m, 2H), 1.40–0.88 (m, 15H) ppm; 13C NMR (100 MHz, CDCl3): δ = 189.4, 170.2, 165.8, 154.6, 152.4, 143.7, 136.9, 130.3, 129.6 (2C), 128.3 (2C), 126.0, 122.0, 121.4, 119.8, 108.0, 83.1, 52.3, 46.8, 30.5, 30.0, 29.0 (2C), 26.4, 26.0, 25.9 (2C), 25.9, 25.2, 25.2, 22.7, 22.3, 21.6 ppm. IR (mineral oil): 3197, 1760, 1718, 1687 cm−1. Anal. Calcd (%) for C35H42N4O5: C 70.21; H 7.07; N 9.36. Found: C 70.45; H 7.10; N 9.30. MS (ESI+): m/z calcd for C35H42N4O5+H+: 599.32 [M + H+]; found: 599.32.
1,3-Dicyclohexyl-6-(2-hydroxyphenyl)-8-(isopropylamino)-9-(4-methoxybenzoyl)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(3j). Yield: 280 mg (91%); white solid; mp 148–150 °C; 1H NMR (400 MHz, CDCl3): δ = 7.74 (m, 2H), 7.23 (m, 1H), 7.09 (m, 2H), 7.00 (m, 2H), 6.90 (m, 1H), 6.47 (br. s, 1H), 5.34 (d, 1H, J = 8.0 Hz), 3.99 (m, 1H), 3.83 (s, 3H), 3.27 (m, 1H), 2.80 (m, 1H), 2.22–2.12 (m, 2H), 1.92–1.65 (m, 8H), 1.54–1.49 (m, 2H), 1.40–0.83 (m, 14H) ppm; 13C NMR (100 MHz, CDCl3): δ = 188.4, 170.3, 166.0, 163.6, 154.7, 152.3, 142.0, 132.0, 130.6 (2C), 130.3, 125.9, 122.2, 121.5, 120.0, 114.2 (2C), 108.5, 83.2, 55.5, 53.8, 52.3, 47.0, 30.5, 30.0, 29.0 (2C), 26.4, 26.0, 25.9, 25.9, 25.2, 25.2, 22.8, 22.3 ppm. IR (mineral oil): 3183, 3060, 1783, 1760, 1739, 1698 cm−1. Anal. Calcd (%) for C35H42N4O6: C 68.38; H 6.89; N 9.11. Found: C 68.46; H 6.92; N 9.08. MS (ESI+): m/z calcd for C35H42N4O6+H+: 615.32 [M + H+]; found: 615.30.
9-(4-Chlorobenzoyl)-1,3-dicyclohexyl-6-(2-hydroxyphenyl)-8-(isopropylamino)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(3k). Yield: 285 mg (92%); white solid; mp 151–153 °C; 1H NMR (400 MHz, CDCl3): δ = 7.67 (m, 2H), 7.47 (m, 2H), 7.23 (m, 1H), 7.06 (m, 1H), 7.01 (m, 1H), 6.90 (m, 1H), 6.45 (br. s, 1H), 5.67 (d, 1H, J = 4.0 Hz), 3.96 (m, 1H), 3.29 (m, 1H), 2.80 (m, 1H), 2.21–2.07 (m, 2H), 1.95–1.66 (m, 7H), 1.59–1.51 (m, 2H), 1.39–0.85 (m, 15H) ppm; 13C NMR (100 MHz, CDCl3): δ = 188.3, 170.0, 165.4, 154.5, 152.3, 139.3, 137.8, 130.5, 129.5 (2C), 129.3 (2C), 125.9, 122.0, 121.5, 119.9, 107.4, 83.0, 53.8, 52.3, 47.22, 30.5, 30.1, 29.0, 29.0, 26.4, 26.0, 25.9, 25.8, 25.2, 25.2, 22.7, 22.3 ppm. IR (mineral oil): 3281, 3080, 1774, 1721, 1704 cm−1. Anal. Calcd (%) for C34H39ClN4O5: C 65.96; H 6.35; N 9.05. Found: C 66.04; H 6.30; N 9.11. MS (ESI+): m/z calcd for C34H39ClN4O5+H+: 619.27 [M + H+]; found: 619.22.
9-Benzoyl-1,3-dicyclohexyl-6-(2-hydroxyphenyl)-8-(phenylamino)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(3l). Yield: 285 mg (92%); yellow solid; mp 187–189 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.86 (s, 1H), 9.31 (s, 1H), 7.35 (m, 2H), 7.31–7.23 (m, 2H), 7.17 (m, 2H), 7.02 (m, 1H), 6.97–6.89 (m, 3H), 6.84 (m, 1H), 6.74 (m, 3H), 3.89 (m, 1H), 3.08 (m, 1H), 2.20–2.02 (m, 2H), 1.88–0.85 (m, 18H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 189.7, 169.8, 163.8, 154.1, 153.8, 141.8, 140.7, 138.3, 132.1, 129.9, 128.5 (2C), 128.0, 127.8 (2C), 126.2, 123.6, 121.3 (2C), 120.4, 119.0, 116.8, 113.8, 108.5, 82.3, 52.0, 51.0, 30.0, 29.4, 28.8, 28.7, 25.7, 25.3, 25.2, 24.9, 24.8 (2C) ppm. IR (mineral oil): 3398, 3247, 1768, 1723, 1704 cm−1. Anal. Calcd (%) for C37H38N4O5: C 71.83; H 6.19; N 9.06. Found: C 72.15; H 6.07; N 9.10. MS (ESI+): m/z calcd for C37H38N4O5+H+: 619.29 [M + H+]; found: 619.27.
1,3-Dicyclohexyl-9-(4-ethoxybenzoyl)-6-(2-hydroxyphenyl)-8-(phenylamino)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(3m). Yield: 312 mg (94%); yellow solid; mp 187–189 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.85 (s, 1H), 9.20 (s, 1H), 7.34 (m, 2H), 7.24 (m, 1H), 7.01 (m, 1H), 6.93 (m, 3H), 6.83 (m, 1H), 6.75 (m, 3H), 6.66 (m, 2H), 4.09 (q, J = 6.8 Hz, 2H), 3.88 (m, 1H), 3.05 (m, 1H), 2.20–2.02 (m, 2H), 1.88–0.85 (m, 21H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 188.2, 169.9, 163.9, 161.7, 154.1, 153.8, 140.7, 140.5, 131.1, 130.3 (2C), 129.9, 128.2 (2C), 126.2, 123.4, 121.2 (2C), 120.5, 118.9, 116.7, 113.7 (2C), 109.2, 82.3, 63.2, 52.0, 51.0, 30.0, 29.5, 28.8, 28.7, 25.7, 25.3, 25.2, 25.0, 24.8, 24.8, 14.3 ppm. IR (mineral oil): 3354, 3250, 1771, 1720, 1705 cm−1. Anal. Calcd (%) for C39H42N4O6: C 70.68; H 6.39; N 8.45. Found: C 70.89; H 6.43; N 9.01. MS (ESI+): m/z calcd for C39H42N4O6+H+: 663.32 [M + H+]; found: 663.28.
8-(Butylamino)-1,3-dicyclohexyl-9-(4-ethoxybenzoyl)-6-(2-hydroxyphenyl)-1,3,6-triazaspiro[4.4]non-8-ene-2,4,7-trione(3n). Yield: 270 mg (84%) (purity 90%); white solid; mp 130–132 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.81 (s, 1H), 7.64 (m, 2H), 7.22 (m, 2H), 7.13–6.77 (m, 10H), 4.16–4.06 (m, 3H), 3.83 (m, 1H), 3.15 (m, 1H), 2.98 (m, 2H), 2.55 (m, 1H), 2.40 (m, 1H), 2.15–1.96 (m, 3H), 1.87–0.67 (m, 18H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 188.4, 170.3, 163.7, 162.1, 154.1, 153.8, 143.9, 132.5, 130.4 (2C), 129.9, 126.2, 120.6, 118.9, 116.7, 114.3 (2C), 105.0, 82.4, 63.5, 51.9, 50.8, 45.5, 40.6, 32.2, 30.5, 30.2, 29.5, 28.8, 25.8, 25.4, 24.9, 19.2, 19.1, 14.4, 13.6, 13.3 ppm. IR (mineral oil): 3325, 3175, 1773, 1718, 1642 cm−1. Anal. Calcd (%) for C37H46N4O6: C 69.14; H 7.21; N 8.72. Found: C 68.89; H 7.25; N 8.71. MS (ESI+): m/z calcd for C37H46N4O6+H+: 643.35 [M + H+]; found: 643.30.

4. Conclusions

In conclusion, we developed a novel approach to 5-spiro-substituted 3-amino-1,5-dihydro-2H-pyrrol-2-ones based on the thermal decomposition of 1,3-disubstituted urea derivatives of 5-spiro-substituted 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones, which were readily prepared by their reaction with carbodiimides.

Supplementary Materials

The following are available online: General procedures and copies of NMR spectra for all new compounds and the results of preliminary antimicrobial assays.

Author Contributions

Conceptualization, E.E.K.; methodology, E.E.K.; validation, E.E.K., E.A.L.; investigation, E.E.K., E.A.L., E.V.K. (synthetic chemistry), M.V.D. (X-ray analyses); writing—original draft preparation, E.E.K., E.A.L.; writing—review and editing, E.E.K., E.A.L., M.V.D.; visualization, E.E.K.; supervision, E.E.K., A.N.M.; project administration, E.E.K.; funding acquisition A.N.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Russian Science Foundation, grant number 19-13-00290.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The presented data are available in this article.

Acknowledgments

The authors are grateful to the CO-ADD (the Community for Antimicrobial Drug Discovery), funded by the Wellcome Trust (UK) and the University of Queensland (Australia), for the performance of preliminary antimicrobial screening.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of all of the compounds are available from the authors.

References

  1. Zhuang, C.; Miao, Z.; Zhu, L.; Dong, G.; Guo, Z.; Wang, S.; Zhang, Y.; Wu, Y.; Yao, J.; Sheng, C.; et al. Discovery, Synthesis, and Biological Evaluation of Orally Active Pyrrolidone Derivatives as Novel Inhibitors of p53–MDM2 Protein–Protein Interaction. J. Med. Chem. 2012, 55, 9630–9642. [Google Scholar] [CrossRef]
  2. Li, J.; Wu, Y.; Guo, Z.; Zhuang, C.; Yao, J.; Dong, G.; Yu, Z.; Min, X.; Wang, S.; Liu, Y.; et al. Discovery of 1-arylpyrrolidone derivatives as potent p53–MDM2 inhibitors based on molecule fusing strategy. Bioorg. Med. Chem. Lett. 2014, 24, 2648–2650. [Google Scholar] [CrossRef] [PubMed]
  3. Kawasuji, T.; Fuji, M.; Yoshinaga, T.; Sato, A.; Fujiwara, T.; Kiyama, R. 3-Hydroxy-1,5-dihydro-pyrrol-2-one derivatives as advanced inhibitors of HIV integrase. Bioorg. Med. Chem. 2007, 15, 5487–5492. [Google Scholar] [CrossRef]
  4. Ma, K.; Wang, P.; Fu, W.; Wan, X.; Zhou, L.; Chu, Y.; Ye, D. Rational design of 2-pyrrolinones as inhibitors of HIV-1 integrase. Bioorg. Med. Chem. Lett. 2011, 21, 6724–6727. [Google Scholar] [CrossRef]
  5. Cusumano, A.Q.; Pierce, J.G. 3-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones as novel antibacterial scaffolds against methicillin-resistant Staphylococcus aureus. Bioorg. Med. Chem. Lett. 2018, 18, 2732–2735. [Google Scholar] [CrossRef] [PubMed]
  6. Sweeney, N.L.; Hanson, A.M.; Mukherjee, S.; Ndjomou, J.; Geiss, B.J.; Steel, J.J.; Frankowski, K.J.; Li, K.; Schoenen, F.J.; Frick, D.N. Benzothiazole and Pyrrolone Flavivirus Inhibitors Targeting the Viral Helicase. ACS Infect. Dis. 2015, 1, 140–148. [Google Scholar] [CrossRef] [PubMed]
  7. Tobinaga, H.; Kameyama, T.; Oohara, M.; Kobayashi, N.; Ohdan, M.; Ishizuka, N.; Kume, M.; Tomari, M.; Tanaka, Y.; Takahashi, F.; et al. Pyrrolinone derivatives as a new class of P2X3 receptor antagonists. Part 1: Initial structure-activity relationship studies of a hit from a high throughput screening. Bioorg. Med. Chem. Lett. 2018, 28, 2338–2342. [Google Scholar] [CrossRef] [PubMed]
  8. Dhavan, A.A.; Ionescu, A.C.; Kaduskar, R.D.; Brambilla, E.; Dallavalle, S.; Varoni, E.M.; Iriti, M. Antibacterial and antifungal activities of 2,3-pyrrolidinedione derivatives against oral pathogens. Bioorg. Med. Chem. Lett. 2016, 26, 1376–1380. [Google Scholar] [CrossRef]
  9. López-Pérez, A.; Freischem, S.; Grimm, I.; Weiergräber, O.; Dingley, A.J.; López-Alberca, M.P.; Waldmann, H.; Vollmer, W.; Kumar, K.; Vuong, C. Discovery of Pyrrolidine-2,3-diones as Novel Inhibitors of P. aeruginosa PBP3. Antibiotics 2021, 10, 529. [Google Scholar] [CrossRef]
  10. Sakhno, Y.I.; Radchenko, O.V.; Muravyova, E.A.; Sirko, S.M.; Shishkina, S.V.; Musatov, V.I.; Desenko, S.M.; Chebanov, V.A. Synthesis of isoxazolylpyrrolones by three-component reaction of α-ketoglutaric acid or its diethyl ester with 3-amino-5-methylisoxazole and aromatic aldehydes. Chem. Heterocycl. Comp. 2021, 57, 261–265. [Google Scholar] [CrossRef]
  11. Gein, V.L.; Pastukhova, E.V.; Korol, A.N.; Dozmorova, N.V.; Voronina, E.V. Synthesis and Some Transformations of 5-Aryl-4-(4-halogenaroyl)-3-hydroxy-1-cyanomethyl-3-pyrrolin-2-ones. Russ. J. Gen. Chem. 2020, 90, 2225–2229. [Google Scholar] [CrossRef]
  12. Abdul Rashid, F.N.A.; Mohammat, M.F.; Bouchamma, F.E.; Shaameri, Z.; Hamzah, A.S. Facile Reduction of β-Enamino Oxopyrrolidine Carboxylates Mediated by Heterogeneous Palladium Catalyst. Russ. J. Org. Chem. 2020, 56, 1082–1088. [Google Scholar] [CrossRef]
  13. Li, Y.; Ma, J.; Liu, Z.; Jin, D.; Jiao, G.; Guo, Y.; Wang, Q.; Zhou, J.; Sun, R. Fabrication of porous ultrathin carbon nitride nanosheet catalysts with enhanced photocatalytic activity for N- and O-heterocyclic compound synthesis. New J. Chem. 2021, 45, 365–372. [Google Scholar] [CrossRef]
  14. del Corte, X.; López-Francés, A.; Maestro, A.; de Marigorta, E.M.; Palacios, F.; Vicario, J. Brönsted Acid Catalyzed Multicomponent Synthesis of Phosphorus and Fluorine-Derived γ-Lactam Derivatives. J. Org. Chem. 2020, 85, 14369–14383. [Google Scholar] [CrossRef]
  15. Bao-Le, L.; Zhang, H.-Y.; Di, J.-Q.; Zhang, Z.-H. Polyoxometalate immobilized on MOF-5 as an environment-friendly catalyst for the synthesis of poly-functionalized 3-pyrrolin-2-ones. Appl. Organomet. Chem. 2021, 35, e6064. [Google Scholar] [CrossRef]
  16. Liu, T.; Dai, C.; Sang, H.; Chen, F.; Huang, Y.; Liao, H.; Liu, S.; Zhu, Q.; Yang, J. Discovery of dihydropyrrolidones as novel inhibitors against influenza A virus. Eur. J. Med. Chem. 2020, 199, 112334. [Google Scholar] [CrossRef]
  17. Konovalova, V.V.; Maslivets, A.N. Synthesis of Spiro Compounds Based on 1H-Pyrrole-2,3-Diones. Mini Rev. Org. Chem. 2019, 16, 173–192. [Google Scholar] [CrossRef]
  18. Dubovtsev, A.Y.; Silaichev, P.S.; Zheleznova, M.A.; Aliev, Z.G.; Maslivets, A.N. Synthesis of spiro[imidazole-2,2′-pyrroles] by reaction of 4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates with urea. Russ. J. Org. Chem. 2016, 52, 1779–1783. [Google Scholar] [CrossRef]
  19. Dubovtsev, A.Y.; Denislamova, E.S.; Silaichev, P.S.; Dmitriev, M.V.; Maslivets, A.N. Synthesis of Imidazole Spiro Compounds From 5-Alkoxycarbonyl-1H-Pyrrole-2,3-Diones and Phenylurea. Chem. Heterocycl. Comp. 2016, 52, 467–472. [Google Scholar] [CrossRef]
  20. Hutchby, M.; Houlden, C.E.; Ford, J.G.; Tyler, S.N.G.; Gagné, M.R.; Lloyd-Jones, G.C.; Booker-Milburn, K.I. Hindered Ureas as Masked Isocyanates: Facile Carbamoylation of Nucleophiles under Neutral Conditions. Angew. Chem. Int. Ed. 2009, 48, 8721–8724. [Google Scholar] [CrossRef]
  21. Kasatkina, S.O.; Geyl, K.K.; Baykov, S.V.; Boyarskaya, I.A.; Boyarskiy, V.P. Catalyst-free synthesis of substituted pyridin-2-yl, quinolin-2-yl, and isoquinolin-1-yl carbamates from the corresponding hetaryl ureas and alcohols. Org. Biomol. Chem. 2021, 19, 6059–6065. [Google Scholar] [CrossRef]
  22. Furumoto, S. The Synthesis of Carbodiimides from Thioureas and 2-Chlorobenzothiazole. Nippon Kagaku Kaishi/J. Chem. Soc. Japan 1973, 1502–1504. [Google Scholar] [CrossRef]
  23. Lutjen, A.B.; Quirk, M.A.; Barbera, A.M.; Kolonko, E.M. Synthesis of (E)-cinnamyl ester derivatives via a greener Steglich esterification. Bioorg. Med. Chem. 2018, 26, 5291–5298. [Google Scholar] [CrossRef] [PubMed]
  24. Williams, A.; Ibrahim, I.T. Carbodiimide chemistry: Recent advances. Chem. Rev. 1981, 81, 589–636. [Google Scholar] [CrossRef]
  25. Blaskovich, M.A.; Zuegg, J.; Elliott, A.G.; Cooper, M.A. Helping Chemists Discover New Antibiotics. ACS Infect. Dis. 2015, 1, 285–287. [Google Scholar] [CrossRef]
  26. CrysAlisPro, Agilent Technologies, Version 1.171.37.33 (release 27-03-2014).
  27. Dolomanov, O.V.; Bourhis, L.J.; Gildea, R.J.; Howard, J.A.K.; Puschmann, H. OLEX2: A complete structure solution, refinement and analysis program. J. Appl. Cryst. 2009, 42, 339–341. [Google Scholar] [CrossRef]
  28. Sheldrick, G.M. A short history of SHELX. Acta Cryst. 2008, A64, 112–122. [Google Scholar] [CrossRef] [Green Version]
  29. Sheldrick, G.M. Crystal structure refinement with SHELXL. Acta Cryst. 2015, C71, 3–8. [Google Scholar] [CrossRef]
  30. Spek, A.L. PLATON SQUEEZE: A tool for the calculation of the disordered solvent contribution to the calculated structure factors. Acta Cryst. 2015, C71, 9–18. [Google Scholar] [CrossRef] [Green Version]
  31. Stepanova, E.E.; Babenysheva, A.V.; Maslivets, A.N. Five-membered 2,3-dioxo heterocycles: LXXVII. [4 + 2]-Cycloaddition of alkyl vinyl ethers to 3-aroylpyrrolo[2,1-c][1,4]benzoxazine-1,2,4(4H)-triones. Russ. J. Org. Chem. 2011, 47, 937–940. [Google Scholar] [CrossRef]
Molecules 26 07179 g001 550
Figure 1. Biologically active compounds containing 3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (HDP) and 3-amino-1,5-dihydro-2H-pyrrol-2-one (ADP) scaffolds. MDM2—mouse double minute 2 homolog [1,2]; p53—cellular tumor antigen p53 [1,2]; Ki—inhibition constant [1,2]; MIC—minimum inhibitory concentration [9]; CC50—cytotoxic concentration 50% [9]; P. aeruginosa—Pseudomonas aeruginosa [9]; CCRF-CEM—human leukemic lymphoblasts cell line [9].
Figure 1. Biologically active compounds containing 3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (HDP) and 3-amino-1,5-dihydro-2H-pyrrol-2-one (ADP) scaffolds. MDM2—mouse double minute 2 homolog [1,2]; p53—cellular tumor antigen p53 [1,2]; Ki—inhibition constant [1,2]; MIC—minimum inhibitory concentration [9]; CC50—cytotoxic concentration 50% [9]; P. aeruginosa—Pseudomonas aeruginosa [9]; CCRF-CEM—human leukemic lymphoblasts cell line [9].
Molecules 26 07179 g001
Molecules 26 07179 sch001 550
Scheme 1. Retrosynthetic pathways towards ADPs.
Scheme 1. Retrosynthetic pathways towards ADPs.
Molecules 26 07179 sch001
Molecules 26 07179 sch002 550
Scheme 2. Approaches to ADPs: previous [1,2,7,9,10,11,12] and this work’s approach.
Scheme 2. Approaches to ADPs: previous [1,2,7,9,10,11,12] and this work’s approach.
Molecules 26 07179 sch002
Molecules 26 07179 sch003 550
Scheme 3. Synthesis of spiro HDPs 1a–g.
Scheme 3. Synthesis of spiro HDPs 1a–g.
Molecules 26 07179 sch003
Molecules 26 07179 sch004 550
Scheme 4. Proposed mechanism of the reaction for HDPs A with amines.
Scheme 4. Proposed mechanism of the reaction for HDPs A with amines.
Molecules 26 07179 sch004
Molecules 26 07179 sch005 550
Scheme 5. Thermal decomposition of urea.
Scheme 5. Thermal decomposition of urea.
Molecules 26 07179 sch005
Molecules 26 07179 sch006 550
Scheme 6. Reaction of compounds 1a–g with carbodiimides 5a–d.
Scheme 6. Reaction of compounds 1a–g with carbodiimides 5a–d.
Molecules 26 07179 sch006
Molecules 26 07179 sch007 550
Scheme 7. Proposed pathway for the formation of compounds 4a–n.
Scheme 7. Proposed pathway for the formation of compounds 4a–n.
Molecules 26 07179 sch007
Table
Table 1. Reaction of spiro HDP 1a with cyclohexylamine under various conditions.
Table 1. Reaction of spiro HDP 1a with cyclohexylamine under various conditions.
Molecules 26 07179 i001
EntryReagent Ratio (1a:CyNH2) 1SolventTemperature (°C)Time (h)Yield 2 3a (%)
11:1AcOH1181- 3
21:1AcOH11812-
31:1AcOH118120-
41:3AcOH1181-
51:3AcOH11812-
61:1EtOH781-
71:1EtOH7812-
81:3EtOH781-
91:3EtOH7812-
101:11,4-dioxane1011trace
111:31,4-dioxane101120trace
121:1toluene 1131-
131:1toluene11312-
141:3toluene1131-
151:1toluene + HCOOH (1.6 eq.)1131-
1 Reagents and conditions: compound 1a (18.4 µmol, 10 mg), cyclohexylamine, solvent (150 µL), stirring in a screw top V-vial with a solid cap. 2 Determined by UPLC-UV-MS. 3 Not detected by UPLC-UV-MS.
Table
Table 2. Thermal decomposition of compounds 4 1.
Table 2. Thermal decomposition of compounds 4 1.
Molecules 26 07179 i002
EntryArRR’PrecursorsTemperature 2 (°C)Yield 3 (%)
1/245
3aPhHCyaaa280–29096
3bPhHi-Prabb240–25090
3cC6H4OEt-4HCybca230–24093
3dC6H4OMe-4HCycda240–25091
3ePhClCydea270–28090
3fC6H4Me-4HCyefa260–27098
3gC6H4NO2-4HCyfga240–25090
3hC6H4Cl-4HCygha230–24090
3iC6H4Me-4Hi-Preib220–23094
3jC6H4OMe-4Hi-Prcjb230–24091
3kC6H4Cl-4Hi-Prgkb230–24092
3lPhHPhalc160–17092
3mC6H4OEt-4HPhbmc160–17094
3nC6H4OEt-4Hn-Bubnd160–17084
1 Reaction scale: compound 4 (0.5 mmol). 2 Bath temperature. 3 Isolated yields.
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Khramtsova, E.E.; Lystsova, E.A.; Khokhlova, E.V.; Dmitriev, M.V.; Maslivets, A.N. Amination of 5-Spiro-Substituted 3-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones. Molecules 2021, 26, 7179. https://doi.org/10.3390/molecules26237179

AMA Style

Khramtsova EE, Lystsova EA, Khokhlova EV, Dmitriev MV, Maslivets AN. Amination of 5-Spiro-Substituted 3-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones. Molecules. 2021; 26(23):7179. https://doi.org/10.3390/molecules26237179

Chicago/Turabian Style

Khramtsova, Ekaterina E., Ekaterina A. Lystsova, Evgeniya V. Khokhlova, Maksim V. Dmitriev, and Andrey N. Maslivets. 2021. "Amination of 5-Spiro-Substituted 3-Hydroxy-1,5-dihydro-2H-pyrrol-2-ones" Molecules 26, no. 23: 7179. https://doi.org/10.3390/molecules26237179

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