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Abstract

Compounds containing a hydantoin moiety are found in several medicines in clinical use. In this research, ethyl- and methyl-[2-(5-benzylidene)-2,4-dioxoimidazolidin-3-yl]acetyl esters are successfully synthesized over four reaction steps using conventional methods. The synthesis begins by subjecting hydantoin to a Knoevenagel condensation reaction with three different benzaldehydes to afford the penultimate products, which are further reacted with ethyl or methyl (bromoacetyl)alaninates, butanoates, valinates, and norvalinates to give the desired products as esters in low to moderate yields.

Keywords

alaninate hydantoin norvalinate valinate

Introduction

In 2020, Jonnalagadda and co-workers reported that more than 75% of drugs approved by the Food and Drug Administration (FDA) are nitrogen-containing heterocycles.¹ Among the top 25 nitrogen heterocycles in FDA-approved drugs, imidazolidine ranks as number 19 and is found in 11 approved drugs.² Imidazolidine-2,4-dione- or hydantoin-containing compounds are known to exhibit a wide range of pharmacological and biological activities and are used to treat various diseases. Both naturally occurring (Figure 1) and synthetic (Figure 2) hydantoin-containing compounds have been reported to possess biological activity. Among naturally occurring hydantoin-containing compounds, hydantocidin (1) was isolated from the Streptomyces hygroscopicus SANK 63584 and was reported to possess herbicidal activity.³ The ethanolic extract of the Red Sea sponge Hemimycale arabica was found to contain among other compounds 5-[(6-bromo-1H-indol-3-yl)methylene]hydantoin (2) which exhibits moderate antiproliferative activity against human cervical carcinoma (HeLa) cells and also displayed antimicrobial activities.⁴ Axinohydantoin (3) was isolated from the sponge Stylotella aurantium and was found to be an inhibitor of protein kinase C.⁵

Figure 1.

Naturally occurring hydantoin-containing compounds.

Figure 2.

Synthetic compounds containing the hydantoin moiety.

Synthetic compounds containing the hydantoin moiety have also been reported to possess different biological activities. Among these are anticonvulsive agents such as phenytoin (4),⁶ antimicrobial agents such as nitrofurantoin (5),⁷ antiarrhythmic agents such as azimilide (6),⁸ and the nonsteroidal antiandrogen nilutamide (7) which has been reported for the treatment of prostate cancer.⁹ This information strengthens the necessity of synthesizing compounds containing five-membered heterocycles such as hydantoin. Many more hydantoin-containing compounds, both naturally occurring and synthetic, have been reported in reviews.^10,11

Encouraged by the results obtained in our previous study with 2,4-thiazolidinedione (Figure 3) in the synthesis of 5-benzylidene-2,4-thiazolidinedione esters,¹² we sought to expand this study by replacing a 2,4-thiazolidinedione moiety with a hydantoin moiety for the synthesis of new 5-benzylidene hydantoin esters (Scheme 1).

Figure 3.

A schematic diagram of reported and newly synthesized compounds.

Scheme 1.

Synthesis of ethyl or methyl [2-(5-benzylidene)-2,4-dioxoimidazolidin-3-yl]acetyl esters.

The 5-benzylidene-2,4-thiazolidinedione esters synthesized in our previous work had been tested for their antidiabetic activity on the alpha-glucosidase (unpublished results). Our results indicated that compounds synthesized from para-substituted benzaldehyde had better activity than any other compounds; hence, this research also focused on the usage of 4-methoxybenzaldehyde, 4-methylbenzaldehyde, and the piperonal in the Knoevenagel condensation step.

Unlike the compounds prepared using 2,4-thiazolidinedione, this study starts with the Knoevenagel condensation of three different benzaldehydes with hydantoin as reported by Chung and co-workers.¹³ The resulting benzylidene hydantoins 8a–c are then reacted with ethyl or methyl (2-bromoacetyl)alaninate, -valinate, -butanoate, or -norvaline 9a–d to give the desired products 10a–o (Scheme 1).

Reagents and conditions include (1) hydantoin, piperidine, reflux, 7 h, (2) SOCl₂, EtOH, or MeOH, reflux, (3) bromoacetyl chloride, H₂O/DCM (1:1), K₂CO₃, −10 °C to r.t. 16 h, and (4) KOH, MeOH, reflux, 4 h.

Results and discussion

The synthesis of the desired ethyl or methyl [2-(5-benzylidene)-2,4-dioxoimidazolidin-3-yl]acetyl esters began by reacting commercial hydantoin with different benzaldehydes to give benzylidene hydantoins 8a–c in reasonable yields.¹³ These compounds were characterized by NMR spectroscopy; the ¹H NMR spectra of the three compounds exhibited the benzylidene protons signals at 6 parts per million (ppm) confirming successful condensation reactions. The same spectra also showed the presence of two singlet peaks accounting for one proton each ~10.2 ppm (ascribed to the imide proton at position 3 of the hydantoin moiety) and ~11.5 ppm (ascribed to the amide proton at position 1 of the hydantoin moiety). In the ¹³C NMR spectra of compounds 8a–c, the benzylidene carbon signals were observed ~109 ppm.

Concurrently, compounds 9a–d were synthesized by first protecting the amino acids with thionyl chloride in the presence of ethanol¹² or methanol¹⁴ and subsequently reacting the intermediates with bromoacetyl chloride in the presence of potassium carbonate to afford compounds 9a–d in good yields. Finally, substitution reactions between benzylidenehydantoins 8 and compounds 9 followed by crystallization from acetone afforded the targeted ethyl or methyl [2-(5-benzylidene)-2,4-dioxoimidazolidin-3-yl]acetyl esters 10a–o in low to moderate yields (Figure 4). These compounds were characterized by NMR and IR spectroscopy together with mass spectroscopic analysis. ¹H NMR spectra of the products showed the presence of one NH signal at ~ 10.7 ppm consistent with mono-N-alkylation. The regioselectivity of N-alkylation of hydantoins 8 at the 3-position was established by analogy with the literature.¹⁵ Bases such as potassium hydroxide lead to selective alkylation at the more acidic 3-position; only stronger bases that effect double deprotonation give alkylation at the more hindered 1-position.¹⁶ This confirmed that the hydrogen at position 3 had been replaced by compounds 9. Also in the ¹H NMR spectra of these compounds, doublets accounting for one proton ~ 8.7 ppm were observed confirming the presence of the amidic proton. The spectra were also characterized by a singlet accounting for two protons ~4.1 ppm confirming the methylene protons adjacent to the ring nitrogen. The ¹³C NMR spectra of compounds 10 were characterized by four carbonyl carbon signals and a methylene carbon resonance ~ 40 ppm.

Figure 4.

Structures of the synthesized benzylidene-hydantoin esters, 10a–o.

Conclusion

In summary, we have reported the synthesis of 5-benzylidenehydantoin esters. The Knoevenagel condensation of hydantoin and subsequent reactions of protected amino acids with bromoacetyl chloride afforded the desired products. Thus, this protocol provides rapid access to novel benzylidene compounds and could be of some medicinal chemistry value. Therefore, in the future, these compounds will be evaluated for their antidiabetic activities.

Experimental

All reagents used were of analytical grade from Sigma-Aldrich and Fluka. Thin-layer chromatography (TLC) was carried out using Macherey-Nagel Alugram Sil G/UV₂₅₄ plates, pre-coated with 0.25 mm silica gel 60. Detection was performed under ultraviolet light at 254 nm. ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded on a Bruker 400 MHz spectrometer using DMSO-d₆ or CDCl₃ as the solvent and TMS (0.00 ppm) as an internal standard. The values for the chemical shifts are expressed in ppm. The following abbreviations are used: br.s, broad singlet; s, singlet; d, doublets; dd, doublet of doublets; q, quartet; quin, quinet; and m, multiplet; coupling constants (J) are measured in hertz (Hz). Melting points were determined on a Buchi B-540 melting point apparatus using capillary tubes. Infrared spectra were run on a Bruker Platinum 22 Vector Fourier Transform spectrometer (FTIR). Mass spectra (high resolution) were recorded on a Waters GCT mass spectrometer using a Restek Rxi Wintegra Guard column (15 m, 0.25 mm ID, 0.25 µm film thickness). The samples were dissolved in acetonitrile and injected (1 µL) in mode 10:1 at a temperature of 280 °C. The source temperature was 100 °C and the desolvation temperature was set at 300 °C. Helium gas was used as the carrier gas. The software used to control the hyphenated system and to perform all data manipulation was MassLynx 4.1 (SCN 704).

General procedure for the synthesis of (Z)-5-benzylidene hydantoins (8a–c)

These compounds were synthesized from the reaction of hydantoin and appropriate benzaldehydes as described by Chung and co-workers.¹³ Compounds 8a–c were assigned the Z-geometry by comparison with those structures reported in the literature.^17,18

Synthesis of ethyl or methyl (2-bromoacetyl)esters (9a–d)

These compounds were synthesized from their respective amino esters as described by Tshiluka et al.¹² or Barman et al.¹⁴

General procedure for the synthesis of ethyl or methyl 2-(2,4-dioxoimidazolidin-3-yl)acetamido esters (10a–o)

A mixture of arylidene hydantoins 8 (1 mmol) and potassium hydroxide (1 mmol) in methanol was agitated at ambient temperature for 15 min. Ethyl or methyl (2-bromoacetamido) esters (1 mmol) were added and the mixture refluxed for 2–4 h. After the mixture was allowed to cool to room temperature, a precipitate was formed and was collected by filtration. Desired products 10a–o were purified by recrystallization from acetone.

Methyl (2-(5-(4-methoxybenzylidene)-2,4-dioxoimidazolidin-3-yl)acetyl)alaninate (10a):

The reaction of 5-(4-methoxybenzylidene)hydantoin (8a) (0.84 g, 3.85 mmol) and methyl (2-bromoacetyl)alaninate (0.69 g, 3.85 mmol) gave compound 10a as a yellow solid (0.68 g, 47%); m.p. = 264.2–267.8 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.77 (s, 1H, ring-NH), 8.71 (d, 1H, J = 7.2 Hz, NH), 7.63 (d, 2H, J = 8.4 Hz, 2×ArH), 6.95 (d, 2H, J = 8.8 Hz, 2×ArH), 6.54 (s, 1H, =CH), 4.30 (quin, 1H, J = 6.8 Hz, CHNH), 4.13 (s, 2H, CH₂N), 3.81 (s, 3H, ArOCH₃), 3.63 (s, 3H, OCH₃), 1.29 (d, 3H, J = 7.2 Hz, CH₃CH). ¹³C NMR (100 MHz, DMSO-d₆): δ 173.2 (C=O), 166.3 (C=O), 164.5 (C=O), 160.1 (ArC-OCH₃), 155.2 (C=O), 131.7 (2×ArCH), 125.7 (ArC), 125.2 (ArC), 114.8 (2×ArCH), 110.6 (ArylCH), 55.8 (ArOCH₃), 52.4 (CHNH), 48.2 (OCH₃), 40.8 (CH₂N), 17.5 (CH₃CH). IR (KBr): 3286 (N–H), 2955 (C–H), 1762 (C=O), 1741 (C=O), 1601 (C=C), 1115 (C–O) cm⁻¹. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₇H₂₀N₃O₆: 362.1274; found: 362.1234.

Methyl 2-(2-(5-(4-methoxybenzylidene)-2,4-dioxoimidazolidin-3-yl)acetamido)butanoate (10b):

The reaction of 5-(4-methoxybenzylidene)hydantoin (8a) (1.00 g, 4.58 mmol) and methyl 2-(2-bromoacetamido)butanoate (0.95 g, 4.58 mmol) gave compound 10b as a yellow solid (0.71 g, 40%); m.p. = 258–262 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.75 (s, 1H, ring-NH), 8.64 (d, 1H, J = 7.6 Hz, NH), 7.63 (d, 2H, J = 8.4 Hz, ArH), 6.98 (d, 2H, J = 8.4 Hz, ArH), 6.54 (s, 1H, =CH), 4.21 (quin, 1H, J = 5.6 Hz, CHNH), 4.15 (s, 2H, CH₂N), 3.81 (s, 3H, ArOCH₃), 3.64 (s, 3H, OCH₃), 1.75–1.70 (m, 1H, CH_aCH₃), 1.67–1.62 (m, 1H, CH_bCH₃), 0.89 (t, 3H, J = 7.2 Hz, CH₃CH₂). ¹³C NMR (100 MHz, DMSO-d₆): δ 172.7 (C=O), 166.6 (C=O), 164.4 (C=O), 160.1 (ArC-OCH₃), 155.2 (C=O), 131.7 (2×ArCH), 125.6 (ArC), 124.7 (ArC), 114.8 (2×ArCH), 110.6 (ArylCH), 55.8 (Ar-OCH₃), 53.9 (CHNH), 52.3 (OCH₃), 40.7 (CH₂N), 25.1 (CH₂CH₃), 10.6 (CH₃CH₂). IR (KBr): 3287 (N–H), 2972 (C–H), 1785 (C=O), 1739 (C=O), 1601 (C=C), 1169 (C–O) cm⁻¹. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₈H₂₂N₃O₆: 376.1430; found: 376.1495.

Methyl (2-(5-(4-methoxybenzylidene)-2,4-dioxoimidazolidin-3-yl)acetyl)valinate (10c):

The reaction of 5-(4-methoxybenzylidene)hydantoin (8a) (0.50 g, 2.29 mmol) and methyl (2-bromoacetyl)valinate (0.48 g, 2.29 mmol) gave compound 10c as a brown solid (0.40 g, 44%); m.p. = 259–302 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 10.73 (s, 1H, ring-NH), 8.58 (d, 1H, J = 8.4 Hz, NH), 7.63 (d, 2H, J = 8.8 Hz, 2×ArH), 6.98 (d, 2H, J = 8.8 Hz, 2×ArH), 6.54 (s, 1H, =CH), 4.36–4.12 (m, 3H, CHNH + CH₂N), 3.81 (s, 3H, Ar-OCH₃), 3.66 (s, 3H, OCH₃), 2.20 (m, 1H, CH(CH₃)₂), 0.89 (t, 6H, J = 7.2 Hz, CH(CH₃)₂). ¹³C NMR (100 MHz, DMSO-d₆): δ 172.2 (C=O), 166.7 (C=O), 164.4 (C=O), 160.1 (ArC-OCH₃), 155.2 (C=O), 131.7 (2×ArCH), 125.7 (ArC), 125.2 (ArC), 114.8 (2×ArCH), 110.6 (ArylCH), 58.0 (CHNH), 55.8 (ArOCH₃), 48.2 (OCH₃), 40.7 (CH₂N), 30.6 (CH(CH₃)₂), 19.4 ((CH₃)₂CH), 18.6 ((CH₃)₂CH); IR (KBr): 3296 (N–H), 2969 (C–H), 1769 (C=O), 1740 (C=O), 1604 (C=C), 1213 (C–O) cm⁻¹; HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₉H₂₄N₃O₆: 390.1587; found: 390.1638.

Ethyl (2-(5-(4-methoxybenzylidene)-2,4-dioxoimidazolidin-3-yl)acetyl)norvalinate (10d):

A reaction of 5-(4-methoxybenzylidene)hydantoin (8a) (1.00 g, 4.58 mmol) and ethyl (2-bromoacetyl)norvalinate (1.02 g, 4.58 mmol) gave compound 10d as a brown solid (0.82 g, 44%); m.p. = 210.8–219.6 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.77 (s, 1H, ring-NH), 8.72 (d, 1H, J = 7.6 Hz, NH), 7.66 (d, 2H, J = 8.8 Hz, 2×ArH), 6.97 (d, 2H, J = 8.4 Hz, 2×ArH), 6.49 (s, 1H, =CH), 4.27 (quin, 1H, J = 5.6 Hz, CHNH), 4.26 (s, 2H, CH₂N), 4.13 (q, 2H, J = 3.6 Hz, OCH₂CH₃), 3.81 (s, 3H, OCH₃), 1.70–1.61 (m, 2H, CH₂CH), 1.29–1.21 (m, 2H, CH₂CH₃), 1.20 (t, 3H, J = 4.0 Hz, CH₃CH₂O), 0.87 (t, 3H, J = 7.2 Hz, CH₃CH₂); ¹³C NMR (100 MHz, DMSO-d₆): δ 172.9 (C=O), 166.8 (C=O), 164.9 (C=O), 159.9 (ArC-OCH₃), 155.8 (C=O), 131.7 (2×ArCH), 126.6 (ArC), 126.1 (ArC), 114.7 (2×ArCH), 110.6 (ArylCH), 62.0 (OCH₂CH₃), 58.9 (CHNH), 55.7 (OCH₃), 40.5 (CH₂N), 33.5 (CH₂CH), 18.9 (CH₂CH₃), 14.6 (CH₃CH₂O), 13.9 (CH₃CH₂); IR (KBr): 3280 (N–H), 2957 (C–H), 1789 (C=O), 1743 (C=O), 1600 (C=C), 1210 (C–O) cm⁻¹. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₀H₂₆N₃O₆: 404.1743; found: 404.1463.

Methyl (2-(5-(4-methylbenzylidene)-2,4-dioxoimidazolidin-3-yl)acetyl)alaninate (10e):

The reaction of 5-(4-methylbenzylidene)hydantoin (8b) (0.28 g, 1.38 mmol) and methyl (2-bromoacetyl)alaninate (0.25 g, 1.38 mmol) gave compound 10e as a yellow solid (0.12 g, 25%); m.p. = 215–234 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.84 (s, 1H, ring-NH), 8.75 (d, 1H, J = 6.8 Hz, NH), 7.57 (d, 2H, J = 8.0 Hz, 2×ArH), 7.23 (d, 2H, J = 8.0 Hz, 2×ArH), 6.45 (s, 1H, =CH), 4.32 (quin, 1H, J = 8.0 Hz, CHNH), 4.22 (s, 2H, CH₂N), 3.63 (s, 3H, OCH₃), 2.43 (s, 3H, ArCH₃), 1.29 (d, 3H, J = 7.2 Hz, CH₃CH); ¹³C NMR (100 MHz, DMSO-d₆): δ 173.3 (C=O), 166.5 (C=O), 164.6 (C=O), 155.5 (C=O), 138.8 (ArC-Me), 130.6 (ArC), 129.9 (2×ArCH), 128.8 (2×ArCH), 110.2 (ArylCH), 52.4 (OCH₃), 48.17 (CHNH), 40.5 (CH₂N), 21.4 (ArCH₃), 17.5 (CH₃CH); IR (KBr): 3291 (N–H), 2942 (C–H), 1770 (C=O), 1741 (C=O), 1604 (C=C), 1158 (C–O) cm⁻¹. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₇H₂₀N₃O₅: 346.1325; found: 346.1383.

Methyl 2-(2-(5-(4-methylbenzylidene)-2,4-dioxoimidazolidin-3-yl)acetamido)butanoate (10f):

The reaction of 5-(4-methylbenzylidene)hydantoin (8b) (0.28 g, 1.38 mmol) and methyl 2-(2-bromoacetamido)butanoate (0.27 g, 1.38 mmol) gave compound 10f as a white solid (0.14 g, 28%); m.p. = 264–266 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.76 (s, 1H, ring-NH), 8.67 (d, 1H, J = 7.2 Hz, NH), 7.55 (d, 2H, J = 8.0 Hz, 2×ArH), 7.22 (d, 2H, J = 8.0 Hz, 2×ArH), 6.53 (s, 1H, =CH), 4.22 (quin, 1H, J = 8.0 Hz, CHNH), 4.16 (s, 2H, CH₂N), 3.63 (s, 3H, OCH₃), 2.42 (s, 3H, ArCH₃), 1.90–1.71 (m, 1H, CH_aCH₃), 1.67–1.56 (m, 1H, CH_bCH₃), 0.88 (t, 3H, J = 7.2 Hz, CH₃CH₂). ¹³C NMR (100 MHz, DMSO-d₆): δ 173.3 (C=O), 166.6 (C=O), 164.5 (C=O), 155.3 (C=O), 138.9 (ArC-Me), 130.4 (ArC), 129.9 (2×ArCH), 129.8 (2×ArCH), 126.4 (ArC), 110.5 (ArylCH), 53.9 (CHNH), 52.3 (OCH₃), 40.6 (CH₂N), 24.9 (CH₂CH₃), 21.4 (ArCH₃), 10.6 (CH₃CH₂). IR (KBr): 3292 (N–H), 2878 (C–H), 1770 (C=O), 1740 (C=O), 1605 (C=C), 1148 (C–O) cm⁻¹. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₈H₂₂N₃O₅: 360.1481; found: 360.1550.

Methyl (2-(5-(4-methylbenzylidene)-2,4-dioxoimidazolidin-3-yl)acetyl)valinate (10g):

A reaction of 5-(4-methylbenzylidene)hydantoin (8b) (0.21 g, 1.04 mmol) and methyl (2-bromoacetyl)valinate (0.22 g, 1.04 mmol) gave compound 10g as a yellow solid (0.14 g, 37%); m.p. = 224–243 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.80 (s, 1H, ring-NH), 8.62 (d, 1H, J = 8.0 Hz, NH), 7.56 (d, 2H, J = 8.0 Hz, 2×ArH), 7.23 (d, 2H, J = 8.0 Hz, 2×ArH), 6.53 (s, 1H, =CH), 4.22–4.10 (m, 3H, CHNH + CH₂N), 3.66 (s, 3H, OCH₃), 2.33 (s, 3H, ArCH₃), 2.05 (quin, 1H, J = 6.8 Hz, CH(CH₃)₂), 0.89 (t, 6H, J = 6.8 Hz, (CH₃)₂CH). ¹³C NMR (100 MHz, DMSO-d₆): δ 172.4 (C=O), 166.7 (C=O), 164.4 (C=O), 155.3 (C=O), 139.0 (ArC-Me), 130.4 (ArC), 130.0 (2×ArCH), 129.9 (2×ArCH), 126.3 (ArC), 110.5 (ArylCH), 58.0 (CHNH), 52.2 (OCH₃), 41.0 (CH₂N), 30.6 (CH(CH₃)₂), 21.4 (ArCH₃), 19.36 ((CH₃)₂CH), 18.58 ((CH₃)₂CH); IR (KBr): 3297 (N–H), 2962 (C–H), 1771 (C=O), 1740 (C=O), 1609 (C=C), 1148 (C–O) cm⁻¹. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₉H₂₄N₃O₅: 396.1538; found: 396.1521.

Methyl (2-(5-(4-methylbenzylidene)-2,4-dioxoimidazolidin-3-yl)acetyl)norvalinate (10h):

The reaction of 5-(4-methylbenzylidene)hydantoin (8b) (0.22 g,1.09 mmol) and methyl (2-bromoacetyl)norvalinate (0.22 g, 1.09 mmol) gave compound 10h as a yellow solid (0.12 g, 30%); m.p. = 240–253 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.80 (s, 1H, ring-NH), 8.66 (d, 1H, J = 7.6 Hz, NH), 7.56 (d, 2H, J = 8.0 Hz, 2×ArH), 7.23 (d, 2H, J = 8.0 Hz, 2×ArH), 6.54 (s, 1H, =CH), 4.26 (quin, 1H, J = 8.0 Hz, CHNH), 4.15 (s, 2H, CH₂N), 3.64 (s, 3H, OCH₃), 2.42 (s, 3H, ArCH₃), 1.72–1.61 (m, 2H, CH₂CH), 1.60–1.56 (m, 2H, CH₂CH₃), 0.89 (t, 3H, J = 7.2 Hz, CH₃CH₂); ¹³C NMR (100 MHz, DMSO-d₆): δ 172.8 (C=O), 166.5 (C=O), 164.4 (C=O), 155.22 (C=O), 139.0 (ArC-Me), 130.4 (ArC), 130.0 (2×ArCH), 129.9 (2×ArCH), 126.9 (ArC), 110.5 (ArylCH), 52.3 (CHNH), 52.2 (OCH₃), 40.6 (CH₂N), 33.5 (CH₂CH), 21.4 (ArCH₃), 19.1 (CH₂CH₃), 13.9 (CH₃CH₂). IR (KBr): 3290 (N–H), 2957 (C–H), 1784 (C=O), 1740 (C=O), 1602 (C=C), 1097 (C–O) cm⁻¹. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₈H₂₄N₃O₅: 374.1638; found: 374.1710.

Ethyl (2-(5-(4-methylbenzylidene)-2,4-dioxoimidazolidin-3-yl)acetyl)alaninate (10i):

The reaction of 5-(4-methylbenzylidene)hydantoin (8b) (0.12 g, 0.59 mmol) and ethyl (2-bromoacetyl)alaninate (0.12 g, 0.59 mmol) gave compound 10i as a white solid (0.12 g, 57%); m.p. = 252–257 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.81 (s, 1H, ring-NH), 8.67 (d, 1H, J = 6.8 Hz, NH), 7.56 (d, 2H, J = 8.0 Hz, 2×ArH), 7.24 (d, 2H, J = 8.0 Hz, 2×ArH), 6.53 (s, 1H, =CH), 4.25 (quin, 1H, J = 7.7 Hz, CHNH), 4.13 (s, 2H, CH₂N), 4.08 (q, 2H, J = 7.2 Hz, OCH₂CH₃), 2.34 (s, 3H, ArCH₃), 1.29 (d, 3H, J = 7.2 Hz, CH₃CH), 1.20 (t, 3H, J = 6.8 Hz, CH₃CH₂O); ¹³C NMR (100 MHz, DMSO-d₆): δ 172.7 (C=O), 166.3 (C=O), 164.8 (C=O), 155.5 (C=O), 139.8 (ArC-Me), 130.4 (ArC), 130.0 (2×ArCH), 129.9 (2×ArCH), 110.3 (ArylCH), 61.0 (OCH₂CH₃), 48.3 (CHNH), 40.6 (CH₂N), 21.4 (ArCH₃), 17.5 (CH₃CH), 14.5 (CH₃CH₂O); IR (KBr): 3289 (N–H), 2916 (C–H), 1763 (C=O), 1718 (C=O), 1604 (C=C), 1185 (C–O) cm⁻¹. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₈H₂₂N₃O₅: 382.1381; found: 382.1386.

Ethyl (2-(5-(4-methylbenzylidene)-2,4-dioxoimidazolidin-3-yl)acetyl)valinate (10j):

The reaction of 5-(4-methylbenzylidene)hydantoin (8b) (0.35 g, 1.73 mmol) and ethyl (2-bromoacetyl)valinate (0.38 g, 1.73 mmol) gave compound 10j as a white solid (0.24 g, 36%); m.p. = 252–257 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.78 (s, 1H, ring-NH), 8.56 (d, 1H, J = 8.0 Hz, NH), 7.55 (d, 2H, J = 8.0 Hz, 2×ArH), 7.24 (d, 2H, J = 8.0 Hz, 2×ArH), 6.53 (s, 1H, =CH), 4.17 (quin, 1H, J = 4.0 Hz, CHNH), 4.14 (s, 2H, CH₂N), 4.07 (q, 2H, J = 7.2 Hz, OCH₂CH₃), 2.34 (s, 3H, ArCH₃), 2.06 (m, 2H, CH(CH₃)₂), 1.18 (q, 3H, J = 7.2 Hz, CH₃CH₂O), 0.90 (t, 6H, J = 6.4 Hz, CH(CH₃)₂). ¹³C NMR (100 MHz, DMSO-d₆): δ 170.8 (C=O), 166.7 (C=O), 164.4 (C=O), 155.2 (C=O), 130.6 (ArC-CH₃), 130.4 (ArC), 130.2 (2×ArCH), 129.9 (2×ArCH), 110.5 (ArylCH), 60.4 (OCH₂CH₃), 58.0 (CHNH), 40.5 (CH₂N), 30.6 (CH(CH₃)₂), 21.2 (ArCH₃), 19.3 (CH(CH₃)₂), 18.5 (CH(CH₃)₂), 14.5 (CH₃CH₂O). IR (KBr): 3210 (N–H), 2921 (C–H), 1769 (C=O), 1714 (C=O), 1606 (C=C), 1145 (C–O) cm⁻¹. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₀H₂₆N₃O₅: 388.1794; found: 388.1856.

Ethyl-(2-(5-(4-methylbenzylidene)-2,4-dioxoimidazolidin-3-yl)acetyl)norvalinate (10k):

The reaction of 5-(4-methylbenzylidene)hydantoin (8b) (1.00 g, 4.95 mmol) and ethyl (2-bromoacetyl)norvalinate (1.10 g, 4.95 mmol) gave compound 10k as a white solid (1.20 g, 63%); m.p. = 242–254 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.80 (s, 1H, ring-NH), 8.66 (d, 1H, J = 8.0 Hz, NH), 7.55 (d, 2H, J = 7.6 Hz, 2×ArH), 7.24 (d, 2H, J = 8.0 Hz, 2×ArH), 6.53 (s, 1H, =CH), 4.23 (quin, 1H, J = 8.0 Hz, CHNH), 4.21 (s, 2H, CH₂N), 4.07 (q, 2H, J = 6.0 Hz, OCH₂CH₃), 2.33 (s, 3H, ArCH₃), 1.71–1.56 (m, 2H, CH₂CH), 1.42–1.35 (m, 2H, CH₂CH₃), 1.21 (t, 3H, J = 7.2 Hz, CH₃CH₂O), 0.87 (t, 3H, J = 7.2 Hz, CH₃CH₂). ¹³C NMR (100 MHz, DMSO-d₆): δ 172.4 (C=O), 166.6 (C=O), 164.5 (C=O), 155.2 (C=O), 139.0 (ArC-CH₃), 130.3 (ArC), 130.0 (2×ArCH), 129.9 (2×ArCH), 126.3 (ArC), 110.5 (ArylCH), 61.0 (OCH₂CH₃), 52.4 (CHNH), 41.0 (CH₂N), 33.5 (CH₂CH), 21.4 (ArCH₃), 18.9 (CH₂CH₃), 14.0 (CH₃CH₂O), 13.9 (CH₃CH₂). IR (KBr): 3291 (N–H), 2957 (C–H), 1786 (C=O), 1740 (C=O), 1608 (C=C), 1119 (C–O) cm⁻¹. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₀H₂₆N₃O₅: 388.1794; found: 388.1864.

Ethyl-(2-(5-(benzo[d][1,3]dioxol-5-ylmethylene)-2,4-dioxoimidazolidin-3-yl)acetyl)alaninate (10l):

The reaction of 5-(benzo[d][1,3]dioxol-5-ylmethylene)hydantoin (8c) (1.00 g, 4.31 mmol) and ethyl (2-bromoacetyl)alaninate (0.83 g, 4.31 mmol) gave 10l as a brown solid (0.51 g, 49%); m.p. = 227–248 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.80 (s, 1H, ring-NH), 8.67 (d, 1H, J = 7.2 Hz, NH), 7.32 (d, 1H, J = 1.4 Hz, ArH), 7.16 (dd, 1H, J = 8.4, 1.2 Hz, ArH), 6.97 (d, 1H, J = 8.0 Hz, ArH), 6.51 (s, 1H, =CH), 6.08 (s, 2H, OCH₂O), 4.30 (quin, 1H, J = 7.6 Hz, CHNH), 4.12 (s, 2H, CH₂N), 4.07 (q, 2H, J = 5.2 Hz, OCH₂CH₃), 1.29 (d, 3H, J = 7.6 Hz, CH₃CH), 1.17 (t, 3H, J = 5.2 Hz, CH₃CH₂O); ¹³C NMR (100 MHz, DMSO-d₆): δ 172.7 (C=O), 166.3 (C=O), 164.4 (C=O), 155.2 (C=O), 148.3 (ArC), 148.2 (ArC), 127.2 (ArC), 125.5 (ArCH), 110.6 (ArylCH), 109.3 (ArCH), 109.2 (ArCH), 101.9 (OCH₂O), 61.2 (OCH₂CH₃), 48.3 (CHNH), 40.5 (CH₂N), 17.5 (CH₃CH), 14.4 (CH₃CH₂O). IR (KBr): 3294 (N–H), 2971 (C–H), 1769 (C=O), 1738 (C=O), 1604 (C=C), 1293 (C–O) cm⁻¹. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₈H₂₀N₃O₇: 390.1223; found: 390.1292.

Ethyl-2-(2-(5-(benzo[d][1,3]dioxol-5-ylmethylene)-2,4-dioxoimidazolidin-3-yl)acetamido)butanoate (10m):

The reaction of (8c) (1.00 g, 4.31 mmol) and ethyl 2-(2-bromoacetamido)butanoate (0.59 g, 4.31 mmol) gave 10m as a brown solid (0.82 g, 47%); m.p. = 244–263 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.75 (s, 1H, ring-NH), 8.62 (d, 1H, J = 7.2 Hz, NH), 7.32 (s, 1H, ArH), 7.17 (d, 1H, J = 8.0 Hz, ArH), 6.97 (d, 1H, J = 8.4 Hz, ArH), 6.51 (s, 1H, =CH), 6.08 (s, 2H, OCH₂O), 4.20–4.06 (m, 5H, CHNH + CH₂N + OCH₂CH₃), 1.77–1.71 (m, 1H, CH_aCH₃), 1.68–1.60 (m, 1H, CH_bCH₃), 1.19 (t, 3H, J = 7.2 Hz, CH₃CH₂O), 0.90 (t, 3H, J = 7.6 Hz, CH₃CH₂); ¹³C NMR (100 MHz, DMSO-d₆): δ 172.1 (C=O), 166.6 (C=O), 164.4 (C=O), 155.2 (C=O), 148.3 (ArC), 148.2 (ArC), 127.3 (ArC), 125.5 (ArCH), 110.6 (ArylCH), 109.3 (ArCH), 109.2 (ArCH), 101.9 (OCH₂O), 61.9 (OCH₂CH₃), 54.0 (CHNH), 40.6 (CH₂N), 24.9 (CH₂CH₃), 14.5 (CH₃CH₂O), 10.6 (CH₃CH₂). IR (KBr): 3294 (N–H), 2971 (C–H), 1769 (C=O), 1738 (C=O), 1714 (C=O), 1658 (C=O), 1604 (C=C), 1293 (C–O) cm⁻¹. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₉H₂₂N₃O₅: 404.1380; found: 404.1461.

Ethyl-(2-(5-(benzo[d][1,3]dioxol-5-ylmethylene)-2,4-dioxoimidazolidin-3-yl)acetyl)valinate (10n):

A reaction of 5-(benzo[d][1,3]dioxol-5-ylmethylene)hydantoin (8c) (1.00 g, 4.31 mmol) and ethyl (2-bromoacetyl)valinate (0.95 g, 4.31 mmol) gave 10n as a brown solid (0.92 g, 51%); m.p. = 221–227 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.78 (s, 1H, ring-NH), 8.58 (d, 1H, J = 8.4 Hz, NH), 7.30 (d, 1H, J = 0.8 Hz, ArH), 7.18 (dd, 1H, J = 7.2, 1.2 Hz, ArH), 6.97 (d, 1H, J = 8.0 Hz, ArH), 6.51 (s, 1H, =CH), 6.08 (s, 2H, OCH₂O), 4.15–4.05 (m, 5H, CHNH + CH₂N + OCH₂CH₃), 2.09–2.00 (m, 1H, CH(CH₃)₂), 1.20 (t, 3H, J = 7.2 Hz, CH₃CH₂O), 0.89 (t, 3H, J = 6.4 Hz, CH(CH₃)₂); ¹³C NMR (100 MHz, DMSO-d₆): δ 171.8 (C=O), 166.6 (C=O), 164.4 (C=O), 155.2 (C=O), 148.3 (ArC), 148.2 (ArC), 127.3 (ArC), 125.5 (ArCH), 110.6 (ArylCH), 109.3 (ArCH), 109.2 (ArCH), 101.9 (OCH₂O), 61.9 (OCH₂CH₃), 58.0 (CHNH), 40.4 (CH₂N), 30.6 (CH(CH₃)₂), 19.3 (CH(CH₃)₂), 18.6 (CH(CH₃)₂), 14.5 (CH₃CH₂O). IR (KBr): 3294 (N–H), 2971 (C–H), 1769 (C=O), 1738 (C=O), 1604 (C=C), 1293 (C–O) cm⁻¹. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₀H₂₄N₃O₇: 418.1536; found: 418.1595.

Methyl-(2-(5-(benzo[d][1,3]dioxol-5-ylmethylene)-2,4-dioxoimidazolidin-3-yl)acetyl)norvalinate (10o):

The reaction of (8c) (1.00 g, 4.31 mmol) and methyl (2-bromoacetyl)norvalinate (0.95 g, 4.31 mmol) gave 10o as a brown solid (0.62 g, 34%); m.p. = 298–302 °C. ¹H NMR (400 MHz, DMSO-d₆): δ 10.74 (s, 1H, ring-NH), 8.64 (d, 1H, J = 7.6 Hz, NH), 7.31 (d, 1H, J = 1.2 Hz, ArH), 7.19 (dd, 1H, J = 8.0, 1.2 Hz, ArH), 6.97 (d, 1H, J = 8.4 Hz, ArH), 6.52 (s, 1H, =CH), 6.08 (s, 2H, OCH₂O), 4.29 (quin, 1H, J = 8.0 Hz, CHNH), 4.14 (s, 2H, CH₂N), 3.64 (s, 3H, OCH₃), 1.70–1.41 (m, 2H, CH₂CH), 1.38–1.25 (m, 2H, CH₂CH₃), 0.88 (t, 3H, J = 7.6 Hz, CH₃CH₂); ¹³C NMR (100 MHz, DMSO-d₆): δ 172.3 (C=O), 166.6 (C=O), 164.4 (C=O), 155.2 (C=O), 148.3 (ArC), 148.2 (ArC), 127.3 (ArC), 125.4 (ArCH), 110.7 (ArylCH), 109.3 (ArCH), 109.2 (ArCH), 101.9 (OCH₂O), 52.3 (CHNH), 52.2 (OCH₃), 40.5 (CH₂N), 33.6 (CH₂CH), 18.9 (CH₂CH₃), 13.9 (CH₃CH₂); IR (KBr): 3294 (N–H), 2971 (C–H), 1769 (C=O), 1738 (C=O), 1604 (C=C), 1293 (C–O) cm⁻¹. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₉H₂₂N₃O₇: 404.1380; found: 404.1439.

Supplemental Material

sj-docx-1-chl-10.1177_17475198221104183 – Supplemental material for Synthesis of new 5-benzylidene-hydantoin esters

Supplemental material, sj-docx-1-chl-10.1177_17475198221104183 for Synthesis of new 5-benzylidene-hydantoin esters by Ndivhuwo R Tshiluka, Mpelegeng V Bvumbi, Unarine Tshishonga and Simon S Mnyakeni-Moleele in Journal of Chemical Research

Footnotes

Acknowledgements

The authors thank the National Research Foundation (NRF) of South Africa and the Sasol Inzalo Foundation for the scholarships provided to Mr N.R.T. and Ms U.T., the THUTHUKA research funds, and the University of Venda Research and Publication Committee (RPC) for sponsoring this research.

Author contributions

Ms U.T. and Mr N.R.T. are the students who executed the project and synthesized reported compounds whereas Dr M.V.B. and Dr S.S.M.-M. are the supervisors of the projects who conceived the projects.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: Ms U.T. and Mr N.R.T. were funded by the South African National Research Fund (NRF) for their studies. Mr N.R.T. was also funded by Sasol Foundation for his studies.

ORCID iD

Simon S Mnyakeni-Moleele

Supplemental material

Supplemental material for this article is available online.

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