3-Cyclohexyl-6-phenyl-1-(p-tolyl)pyrimidine-2,4(1H,3H)-dione

Abstract

The synthesis of a novel uracil derivative, 3-cyclohexyl-6-phenyl-1-(p-tolyl)pyrimidine-2,4(1H,3H)-dione (4), is reported via a four-component reaction involving an α-chloroketone (1), an aliphatic isocyanate (2), a primary aromatic amine (3) and carbon monoxide. The proposed reaction mechanism involves a Pd-catalyzed carbonylation of 2-chloro-1-phenylethan-1-one (1), leading to a β-ketoacylpalladium key intermediate, and, at the same time, in situ formation of non-symmetrical urea deriving from cyclohexyl isocyanate (2) and p-toluidine (3). After a chemo-selective acylation of the non-symmetrical urea and the subsequent cyclization of the acylated intermediate, 3-cyclohexyl-6-phenyl-1-(p-tolyl)pyrimidine-2,4(1H,3H)-dione (4) is formed. Uracil derivative 4 was isolated in good yield (73%) and fully characterized by ¹H, ¹³C, 2D ¹H-¹³C HSQC and 2D ¹H-¹³C HMBC NMR, FT-IR spectroscopy and GC-MS spectrometry.

1. Introduction

Nitrogen heterocycles and specifically pyrimidines are widespread in many natural biologically active molecules. Uracil represents a valuable six-membered N-heterocycle (Figure 1a) that frequently occurs in nature due to one of the four nucleic bases of RNA [1]. In the discovery of new drugs, uracil derivatives are considered very fascinating molecules, both because of their synthetic accessibility and their drug-like properties thanks to the substituents connected at the N¹, N³, C⁵ and C⁶ positions of the uracil ring [2].

Uracil derivatives have a wide spectrum of pharmacological activities and clinical applications. For example, differently substituted uracils containing a benzoyl moiety exhibit herbicidal activity (saflufenacil, Figure 1b) [3] and alkyl-substituted uracils are often employed as pesticides for treatment of citrus and pineapple plantations (terbacil, Figure 1b) [4]. Regarding their pharmacological properties, many uracil-containing drugs have anti-cancer and antiviral activities (fluorodeoxyuridine and zidovudine, respectively, Figure 1b) [5].

There are many synthetic strategies to achieve the uracil heterocycle. Among the reported methods, the simplest one involves the hydrolysis process of cytosine by adding H₂O to produce uracil and ammonia [1]. However, the most widely used methodology to obtain uracil is via a condensation reaction between urea and maleic acid in fuming sulfuric acid [6]. Moreover, many heterocyclic scaffolds can be achieved by employing carbonylative processes, often palladium catalyzed [7,8,9].

As part of our ongoing interest in the field of metal-catalyzed reactions [10,11,12,13] and more specifically of Pd-catalyzed carbonylative syntheses of heterocycles [14,15,16], herein the multicomponent synthesis of the novel uracil derivative 3-cyclohexyl-6-phenyl-1-(p-tolyl)pyrimidine-2,4(1H,3H)-dione (4, Scheme 1) is reported. Heterocycle 4 was prepared via a palladium-catalyzed carbonylation reaction of α-chloroketone 2-chloro-1-phenylethan-1-one (1) in the presence of cyclohexyl isocianate (2) and p-toluidine (3) under a CO atmosphere [17] (Scheme 1).

2. Results and Discussion

Regarding the reaction mechanism of the multicomponent synthesis of uracil derivative 4, we hypothesize the following pathway: a Pd-catalyzed carbonylation of α-chloroketone 1 firstly affords the β-ketoacylpalladium intermediate 5, that subsequently acylates the non-symmetrical urea 6 [18]. The latter was generated in situ from the nucleophilic addition of p-toluidine 3 to the cyclohexyl isocyanate 2 (Scheme 2).

It should be emphasized that the acylation of urea 6 occurred chemoselectively only at the alkyl-substituted nitrogen atom. The observed selectivity was likely due to the higher nucleophilicity of the alkyl-substituted nitrogen atom compared to the aryl-substituted nitrogen. The subsequent cyclization of intermediate 7, promoted by an intramolecular nucleophilic attack of the aryl-substituted nitrogen to the carbonyl group, afforded the desired uracil derivative 4 through a condensation process [17] (Scheme 2). The resulting 3-cyclohexyl-6-phenyl-1-(p-tolyl)pyrimidine-2,4(1H,3H)-dione 4 was isolated after column chromatography in 73% yield.

The uracil derivative 3-cyclohexyl-6-phenyl-1-(p-tolyl)pyrimidine-2,4(1H,3H)-dione 4 was fully characterized by ¹H, ¹³C, 2D ¹H-¹³C HSQC and 2D ¹H-¹³C HMBC NMR, FT-IR spectroscopy and GC-MS spectrometry (see Supplementary Materials for copies of spectra). The ¹H NMR spectrum of uracil derivative 4, recorded at 25 °C in CDCl₃ solution, shows the presence of a distinctive singlet proton at 5.81 ppm due to the vinylic proton, H-5, (Figure 2) of the uracil moiety, in analogy with the chemical shift of similar uracil derivatives reported in a previous work [17]. The signal at 4.87 ppm, a multiplet similar to a triplet of triplets, was attributed to the axial H1′’’ bonded to the tertiary C-1′’’ of the cyclohexyl substituent. This peak has multiplicity due to a vicinal axial–axial (ax–ax) coupling, ³J = 12.2 Hz, and a vicinal axial–equatorial (ax–eq) coupling, ³J = 3.8 Hz. Other protons belonging to the cyclohexyl ring appear in the spectrum as follows. (a) The two equivalents axial protons H-2′’’ resonate at 2.46 ppm, the signal is a multiplet resembling a quartet of doublets. The multiplicity (qd) comes from three couplings of similar magnitude (12.2 Hz, one geminal (²J), two vicinal (axial–axial) with H-3′’’ and H-1′’’) and a smaller coupling (³J = 3.8 Hz) corresponding to a vicinal axial–equatorial interaction with H-3′’’. (b) Four multiplets are observed in the range from 1.84 to 1.16 ppm relative to the remaining 8H of the cyclohexyl ring. (c) Finally, the singlet at 2.25 ppm was clearly assigned to the methylic protons of the p-tolyl moiety (see Supplementary Material for a copy of the ¹H NMR spectrum).

The ¹³C NMR spectrum shows the presence of four characteristic signals belonging to the carbons of the uracil ring: (1) The carbonyl carbon C4 resonates at 162.9, as confirmed by the coupling with protons H-5 and H-1′’’ observed in the HMBC spectrum. (2) The carbonyl carbon C-2 resonates at 152.0 ppm and appears as a broad signal, likely because of the bonds with quadrupolar nuclei N-1 and N-2. Its proximity to the cyclohexyl ring was proven by an intense cross peak with the proton H-1′’’ (HMBC). (3) The peak at 103.3 ppm was assigned to the C-5 of the uracil nucleus based on its coupling with H-5 observed in the HSQC spectrum. (4) The resonance of carbon C-6 was assigned to the peak at 153.9 ppm and confirmed by a cross peak with protons H-5 and H-2′’ (HMBC). (See Supplementary Materials for copies of the ¹³C NMR, 2D HSQC and 2D HMBC spectra.)

3. Materials and Methods

3.1. General Methods

NMR spectra were recorded on a Bruker 500 MHz spectrometer and chemical shifts were reported in parts per million (δ). The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, quin = quintuplet, sext = sextet, sep = septet and br = broad. The FT-IR spectrum was recorded on a Perkin-Elmer 681 spectrometer. GC-MS analyses were performed on a HP 5995C model. Analytical thin-layer chromatography (TLC) was carried out on pre-coated 0.25 mm thick plates of Kieselgel 60 F254, and visualization was accomplished by UV light (254 nm) or by spraying a solution of 5% (w/v) ammonium molybdate and 0.2% (w/v) cerium(III) sulfate in 100 mL 17.6% (w/v) aq. sulfuric acid and heating to 473 K until blue spots appeared. Chromatography was conducted using silica gel 60 with a particle size distribution of 40–63 μm and 230–400 ASTM. Reagents and solvents, unless otherwise specified, were purchased from Sigma-Aldrich (Sigma-Aldrich, St. Louis, MO, USA) and TCI (Tokyo Chemical Industry, Europe, N. V., Eschborn, Germany) and used without any further purification. Petroleum ether refers to the 40–60 °C boiling fraction.

3.2. Synthesis of 3-Cyclohexyl-6-phenyl-1-(p-tolyl)pyrimidine-2,4(1H,3H)-dione (4)

A solution containing cyclohexyl isocyanate 2 (125.2 mg, 128 μL, 1.0 mmol), 2-chloro-1-phenylethan-1-one 1 (463.8 mg, 3.0 mmol), p-toluidine 3 (160.7 mg, 1.5 mmol), Pd(AcO)₂ (trimeric, FW = 673.46, 4 mol%, 27.0 mg, 0.04 mmol), PPh₃ (83.9 mg,0.32 mmol) and NEt₃ (202.4 mg, 278 μL, 2.0 mmol) in anhydrous THF (15 mL) was placed in a 45 mL autoclave. The autoclave was purged three times and pressurized with CO at 27 atm. Then, the reactor was heated at 110 °C under magnetic stirring for 10 h. After this time, the reaction system was cooled to room temperature, carefully depressurized and the solvent was evaporated under reduced pressure to give a crude material. The crude mixture was purified by column chromatography on silica gel using petroleum ether/AcOEt 80:20 as the eluent, affording 3-cyclohexyl-6-phenyl-1-(p-tolyl)pyrimidine-2,4(1H,3H)-dione (4) as a clear yellow oil (263.2 mg, 73% yield).

¹H NMR (400.12 MHz, CDCl₃): δ 7.24–7.22 (m, 1H), 7.19–7.16 (m, 2H), 7.11–7.10 (m, 2H), 7.04–7.03 (m, 2H), 6.95–6.93 (m, 2H), 5.81 (s, 1H), 4.87 (tt, J = 12.2, 3.8 Hz, 1H), 2.46 (qd, J = 12.2, 3.8 Hz, 2H), 2.25 (s, 3H), 1.84–1.82 (m, 2H), 1.73–1.63 (m, 3H), 1.39–1.37 (m, 2H), 1.21–1.16 (m, 1H); ¹³C NMR (100.62 MHz, CDCl₃): δ 162.9, 153.9, 152.0, 138.2, 134.8, 133.5, 129.4, 129.3, 128.9, 128.3, 128.1, 103.3, 54.2, 28.4, 26.3, 25.3, 21.0; FT-IR (film, cm⁻¹): 2931, 2856, 1703, 1657, 1623, 1512, 1447, 1417, 1406, 1360, 1344, 815, 764, 728, 716, 697, 532; GC-MS (70 eV) m/z: 360 (M⁺, 1), 279 (100), 235 (16), 207 (31), 194 (17), 91 (13), 77 (4), 65 (6), 55 (4).

4. Conclusions

The novel uracil derivative 3-cyclohexyl-6-phenyl-1-(p-tolyl)pyrimidine-2,4(1H,3H)-dione (4) was synthetized through a four-component Pd-catalyzed reaction and isolated by column chromatography in good yield (73%). The uracil derivative 4 was fully characterized by ¹H, ¹³C, 2D ¹H-¹³C HSQC and 2D ¹H-¹³C HMBC NMR, FT-IR spectroscopy and GC-MS spectrometry.