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Short Note


Department of Pharmacy, Division of Pharmaceutical Chemistry, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece
Author to whom correspondence should be addressed.
Academic Editors: Dimitrios Matiadis and Eleftherios Halevas
Molbank 2021, 2021(2), M1228;
Received: 18 May 2021 / Revised: 25 May 2021 / Accepted: 1 June 2021 / Published: 4 June 2021


A simple, fast and cost-effective three-step synthesis of 1-methyl-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione has been developed. The reactions described herein proceed readily, with high yields and no further purification. Therefore, the proposed method, with an overall yield of 60%, offers a facile pathway to the synthesis of N-1 monosubstituted spiro carbocyclic imidazolidine-2,4-diones (hydantoins), which constitute a privileged class of heterocyclic scaffolds with pharmacological interest.
Keywords: carbocyclic hydantoins; N-1 substituted hydantoin; spiro hydantoins; imidazolidine-2,4-diones; DFT calculations; stereochemistry; NMR; HRMS; GIAO; ring closing carbocyclic hydantoins; N-1 substituted hydantoin; spiro hydantoins; imidazolidine-2,4-diones; DFT calculations; stereochemistry; NMR; HRMS; GIAO; ring closing

1. Introduction

Hydantoins, or imidazolidine-2,4-diones, is a class of compounds first isolated as a product from allantoin hydrogenolysis in 1861 from the Nobel laureate Adolph von Baeyer. Since then, hydantoin derivatives have become increasingly important, with various applications across chemical and pharmaceutical industries. Although, the hydantoin ring itself possesses no biological activity, 5- and especially 5,5-substituted derivatives have a documented, wide range of therapeutic applications [1]. The most noticeable drugs in this class of compounds showcase anticonvulsant [2], antidiabetic [3], anticancer [4], antiarrhythmic [5] and anti-inflammatory [6] activity. For example, Figure 1 depicts three well-known hydantoins with medicinal applications. Phenytoin exhibits a regulatory effect on the central nervous system (CNS) and has been applied successfully to ameliorating epilepsy symptoms for more than 70 years now and as a treatment of neuropathic pain [7]. More recently, Dantrolene (Figure 1), has been used in the clinical treatment of malignant hyperthermia through the inhibition of abnormal Ca2+ release at the sarcoplasmic reticulum and physiological Ca2+ release from skeletal muscles [8], whilst another compound known as BIRT377 (Figure 1) demonstrates potent anti-inflammatory activity as an antagonist of lymphocyte function-associated antigen-1 (LFA-1) [9]. Therefore, hydantoins are catching the attention of both the medicinal and organic chemistry spectrums based on their facilitated, privileged pharmacological profile [10].
Our medicinal chemistry lab has an active research interest in the development of such molecules incorporating bulky lipophilic carbocyclic rings into the spiro hydantoin core structure. These specific analogs are highly functionalized ‘building blocks’, with significant antiviral and trypanocidal activity, suitable for further synthetic transformations [11].
The introduction of substituents at the N-3 position of the hydantoin ring may be accomplished easily using alkyl halides in an alkaline solution. However, the synthesis of N-1 monosubstituted hydantoins cannot be achieved through direct alkylation unless the N-3 nitrogen is protected. The specified reactivity is explained due to the more activated N-3 position with the two neighboring activating carbonyl groups. In this paper, we report a simple, fast and effective 3-steps synthesis of 1-methyl-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (4). This synthetic route affords pure products in very good yields (overall yield of 60%) that can be used without further purifications. Therefore, the proposed facile and cost-effective method can be generally applied for the synthesis of N-1 monosubstituted spiro carbocyclic hydantoins that are building blocks of high interest to medicinal chemists.

2. Results

The target compound (4), is obtained by following the synthetic procedure shown in Scheme 1. The key intermediate α-amino nitrile hydrochloride (2) was obtained by a Strecker reaction of the bulky commercially available 4-phenylcyclohexan-1-one with NaCN and methylamine hydrochloride in a mixture of DMSO/H2O. After workup, the resulting dry Et2O solution of the free amino nitrile was treated with saturated ethanolic hydrochloric acid solution under ice cooling. 1-(Methylamino)-4-phenylcyclohexane-1-carbonitrile hydrochloride (2) was then treated with potassium cyanate (KOCN) in the presence of acetic acid and water to yield the corresponding ureido derivative (3). Cyclization of the latter with sodium hydride (60% NaH in mineral oil) in dry DMF and subsequent acid hydrolysis led to the target 1-methyl-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (4).
For the target compound (4), a structure optimization step took place in order to determine its energy minima conformation. Starting from the selection of the cyclohexane, two more stable conformations (i.e., chair and twisted boat) [12], we drew the possible four more favorable structures that underwent the ab initio calculation (Figure 2). Although the twisted boat conformation of cyclohexane bears a 23.01 kJ/mol higher energy, it was nonetheless included in our experiments. Additionally, in all of the structures, the phenyl ring always occupies always the equatorial position since the axial position would introduce additional hindering effects on the respective conformations, resulting in even higher energies. Based on our calculations (Table 1), the energy minima for compound (4) resulted in being the conformation B (0 kJ/mol), while on ascending order the rest follow with the second being conformation A (9.43 kJ/mol), third being conformation C (26.08 kJ/mol) and fourth being conformation D (30.83 kJ/mol). Additional information upon all minimized conformers regarding bond lengths, angles and dihedrals can be found on Supplementary Tables S1–S4.
Based on the NMR of compound (4), provided on the supporting information, stereochemistry as determined from the data for the 3D structure with HMBC and NOESY (Figure 3a), correlations verify that the experimentally obtained structure matches the calculated energy minima conformation B. On the contrary Gauge-Independent Atomic Orbital (GIAO), theoretical calculations predicted similar signals for conformations AD (Figure 3b) when referred to the hydantoin and the phenyl rings, respectively. For the cyclohexane ring conformations, A and B represent a more relatively true estimation, with two signals for carbons C7,9 and C6,10.

3. Materials and Methods

3.1. Chemistry

Materials, apparatuses and techniques for the experimental part are as follows. Melting points were determined using a Büchi capillary apparatus and are uncorrected. NMR experiments were performed to elucidate the structure and determine the purity of the newly synthesized compounds. 1H NMR and 2D NMR spectra (COSY, HSQC-DEPT, HMBC) were recorded on a Bruker Ultrashield™ Plus Avance III 600 spectrometer (150.9 MHz, 13C NMR). Chemical shifts δ (delta) are reported in parts per million (ppm) downfield from the NMR solvent, with the tetramethylsilane or solvent (DMSO-d6) as internal standard. Data processing including Fourier transformation, baseline correction, phasing, peak peaking and integrations were performed using MestReNova software v.12.0.0. Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; dd, doublet of doublets; td, triplet of doublets; m, multiplet; complex m, complex multiplet. Coupling constants (J) are expressed in units of Hertz (Hz). The spectra were recorded at 293 K (20 °C) unless otherwise specified. The solvent used to obtain the spectra was deuterated DMSO, DMSO-d6 (quin, 2.50 ppm, 1H NMR; septet, 39.52 ppm, 13C NMR). IR spectra were recorded on a Perkin Elmer Spectrum BX FT-IR FTIR Spectrophotometer. Analytical thin-layer chromatography (TLC) was used to monitor the progress of the reactions, as well as to authenticate the compounds. TLCs were conducted on and precoated with normal-phase silica gel, aluminum sheets (Silica gel 60 F254, Merck) (layer thickness 0.2 mm), precoated with reverse-phase silica gel, aluminum sheets (Silica gel 60 RP-18 F254s, Merck) and precoated aluminum oxide plates (TLC Aluminium oxide 60 F254, neutral). Developed plates were examined under a UV light source, at wavelengths of 254 nm or after being stained by iodine vapors. The Retention factor (Rf) of the newly synthesized compounds, which equals to the distance migrated over the total distance covered by the solvent, was also measured on the chromatoplates. Elemental analyses (C, H, N) were performed by the Service Central de Microanalyse at CNRS (Paris, France), and were within ±0.4% of the theoretical values. Elemental analysis results for the tested compounds correspond to ˃95% purity. The HRMS spectra were acquired in the negative ionization mode, employing a QTOF-MS (Maxis Impact, Bruker Daltonics, Bremen, Germany) using a resolving power of 40,000. The commercial reagents were purchased from Alfa Aesar, Sigma-Aldrich and Merck, and were used without further purification. Solvent abbreviations: ACN, acetonitrile; AcOEt, ethyl acetate; Et2O, diethyl ether; EtOH, ethanol; MeOH, methanol.

3.2. Computational

Density Functional Theory (DFT) calculations are as follows. All in silico calculations were carried out on a typical desktop PC running a Windows 10 64-bit operating system (Intel i7 3.4 GHz CPU processors, RAM 32 GB), in gas phase unless otherwise specified, using the G09W [13] software package. The hybrid DFT method with Becke’s [14] three-parameter functional and the nonlocal correlation provided by the Lee, Yang and Parr expression (B3LYP) [15] was used for optimization, employing the 6−31+G(d,p) basis set [16,17]. Single-point calculations of all structures were also carried out using the same basis set [16,17], following the optimized-geometries step. NMR shielding tensors computed with the GIAO method [18,19,20,21,22] on default parameters for degeneracy tolerance (0.05) in DMSO solvent, including spin–spin coupling constants [23,24,25,26,27].

3.3. Synthesis

1-(Methylamino)-4-phenylcyclohexane-1-carbonitrile hydrochloride (2): To a stirred suspension of sodium cyanide (843 mg, 17.2 mmol) and methylamine hydrochloride (1.16 g, 17.2 mmol) in 12 mL of DMSO/H2O 9:1 (v/v), a solution of 4-phenylcyclohexanone (3.0 g, 17.2 mmol) in DMSO (24 mL) was added in one portion. The reaction mixture was stirred for 46 h at rt, poured into 130 mL of ice–water mixture and extracted with AcOEt (3 × 60 mL). The combined organic phases were washed with brine (2 × 60 mL), dried with anh. Na2SO4 and the solvent was evaporated under reduced pressure. The residue was dissolved in Et2O (80 mL) and treated dropwise with an ethanolic solution saturated with gaseous hydrochloric acid to pH ~2 under ice bath. The precipitate formed was filtered off in vacuo, washed with small portions of dry Et2O and dried over P2O5 to afford the title compound 2 as a white crystalline solid (3.55 g, 80%). This intermediate was used for the next reaction without further purification.
1-(1-Cyano-4-phenylcyclohexyl)-1-methylurea (3): To a stirred solution of the carbonitrile 2 (3.1 g, 12.4 mmol) in 20 mL acetic acid, a solution of potassium cyanate (2.01 g, 24.8 mmol) in 3 mL H2O was added. After stirring for 1 h at 35 °C, the reaction mixture was poured into 70 mL H2O and extracted with CHCl3 (3 × 50 mL). The combined organic layers were washed with H2O (3 × 50 mL) and brine (2 × 50 mL), dried with anh. Na2SO4 and the solvents were evaporated to dryness under reduced pressure to afford the title compound 3 as a white solid (2.97 g, 93%). This intermediate was used for the next reaction without further purification.
1-Methyl-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (4): A stirred solution of 3 (2.9 g, 11.3 mmol) in 40 mL dry DMF was cooled in an ice bath and sodium hydride (353 mg, 14.7 mmol, 60% dispersion in mineral oil) was added portion-wise. After 4 d of stirring at 45 °C under Argon, the mixture was treated with a solution of HCl 10% (96 mL) and stirring was continued for 24 h at 45 °C. After this time, the reaction mixture was poured into 400 mL of ice–water mixture and extracted with CHCl3 (4 × 200 mL). The combined organic extracts were washed with H2O (3 × 250 mL) and brine (2 × 250 mL), dried with anh. Na2SO4 and the solvent was evaporated in vacuo. The remaining solid was treated with Et2O and n-pentane to give the desired compound 4 as a pale yellow crystalline product. (2.44 g, 79%); Rf = 0.34 (CH2Cl2/AcOEt 5:1); mp 211–214 °C (AcOEt/dry Et2O-n-pentane).
1H NMR (600 MHz, DMSO-d6) δ 1.70-1.75 (m, 4H, H6, H7, H9, H10), 1.93 (td, 2H, J = 12.8, 4.3 Hz, H6, H10), 2.18 (qd, 2H, J = 13.1, 3.9 Hz, H7, H9), 2.57 (tt, 1H, J = 12.5, 3.5 Hz, H8), 2.73 (s, 3H, CH3), 7.19 (m, 1H, H4’), 7.24 (m, 2H, H2’, H6’), 7.30 (t, 2H, J = 7.6 Hz, H3’, H5’), 10.73 (s, 1H, H3) ppm.
13C NMR (150 MHz, DMSO-d6) δ 23.1 (CH3), 28.5 (C7, C9), 30.1 (C6, C10), 41.5 (C8), 61.6 (C5), 126.0 (C4’), 126.6 (C2’, C6’), 128.3 (C3’, C5’), 146.4 (C1’), 155.1 (C2=O), 177.3 (C4=O) ppm.
IR (mull) ν 3143.9 (>N-H)amide, 2923.6 (C-H)sp2, 2856.1 (C-H)sp3, 2723.2 (C-H)sp3, 1764.6 (C=O)amide, 1707.5 (C=O)amide, 1459.5 (C=C)Ar, 1406.5 (C=C)Ar, 1376.8 (C-H)methyl, 1141.0 (C-N)methyl, 1118.9 (C-N)spiro, 1067.3 (>CH2) cm−1.
Anal. Calcd for C15H18N2O2: C, 69.74; H, 7.02; N, 10.84. Found: C, 69.90; H, 7.30; N, 10.50. HRMS m/z calc. for C15H18N2O2 [M − H]+ 257.1285, obtained 257.1287.

4. Conclusions

1-Methyl-8-phenyl-1,3-diazaspiro[4.5]decane-2,4-dione (4) was obtained through a facile and cost-effective method that offers a general route for the synthesis of N-1 monosubstituted spiro carbocyclic hydantoins, which are heterocyclic scaffolds of great interest to the pharmaceutical industry. The reactions were executed under mild (rt to 45 °C) and sustainable (intermediates can be used without further purifications) conditions. The structure of compound (4) was determined using 1H NMR, 13C NMR, HSQC, HMBC, elemental analysis, FT-IR and HRMS, while stereochemistry was elucidated from the data for the 3D structure obtained by HMBC, NOESY and DFT energy minima/GIAO calculations.

Supplementary Materials

The following are available online, NMR spectra of (4) in DMSO-d6 (600 MHz) (1H, 13C, COSY, HSQC-DEPT, HMBC, NOESY) p. S3, NMR spectra of (4) in CDCl3 (400 MHz) (1H, 13C, COSY, HSQC-DEPT, HMBC) p.S9, HRMS Spectra of (4), p. S14, FT-IR Spectra of (4), p. S16, Table S1: Conformation A properties p. S17, Table S2: Conformation B properties p. S20, Table S3: Conformation C properties p. S23, Table S4: Conformation D properties p. S26.

Author Contributions

V.P.: investigation; S.K.: DFT calculations, data curation, writing—original draft preparation and editing; E.G.: editing; G.Z.: conceptualization, methodology, data curation, writing—original draft preparation and editing, supervision and funding acquisition. All authors have read and agreed to the published version of the manuscript.


G.Z. would like to thank ‘Empirikion Foundation’ for financial support. V.P. would like to thank the State Scholarships Foundation of Greece for providing her a Ph.D. fellowship (MIS-5000432, NSRF 2014–2020).

Data Availability Statement

Not applicable.


We thank Evangelos Gikas (Laboratory of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens) for performing the HRMS spectra and Dimitra Benaki (Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens) for performing the NMR experiments.

Conflicts of Interest

The authors declare no conflict of interest.


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Figure 1. Chemical structures of hydantoin-containing compounds with important biological activity.
Figure 1. Chemical structures of hydantoin-containing compounds with important biological activity.
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Scheme 1. The proposed facile and cost-effective method applied for the synthesis of N-1 monosubstituted spiro carbocyclic hydantoins.
Scheme 1. The proposed facile and cost-effective method applied for the synthesis of N-1 monosubstituted spiro carbocyclic hydantoins.
Molbank 2021 m1228 sch001
Figure 2. Chemical structure representation of compound (4) conformations (AD).
Figure 2. Chemical structure representation of compound (4) conformations (AD).
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Figure 3. (a) Representation of experimental NMR data for (4) with HMBC correlations illustrated as blue two-way bent arrows and NOESY illustrated as red two-way bent arrows. (b) GIAO predicted 13C NMR chemical shifts of all conformers with black writing and experimental shifts for the assigned conformer B in a blue color.
Figure 3. (a) Representation of experimental NMR data for (4) with HMBC correlations illustrated as blue two-way bent arrows and NOESY illustrated as red two-way bent arrows. (b) GIAO predicted 13C NMR chemical shifts of all conformers with black writing and experimental shifts for the assigned conformer B in a blue color.
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Table 1. DFT summary of the calculated 4 conformations AD.
Table 1. DFT summary of the calculated 4 conformations AD.
CompoundConformation AConformation ΒConformation CConformation D
4 Molbank 2021 m1228 i001 Molbank 2021 m1228 i002 Molbank 2021 m1228 i003 Molbank 2021 m1228 i004
E(RB3LYP)-842.498395 Hartree-842.501986 Hartree-842.492052 Hartree-842.490242 Hartree
RMS Gradient Norm----
Imaginary Freq----
Dipole Moment3.3648443.032529 Debye3.042446 Debye3.364416 Debye
Point GroupC1C1C1C1
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