3-Benzoyl-1′,3′,6-trimethyl-2′H,3H,4H-spiro[furo[3,2-c]pyran-2,5′-pyrimidine]-2′,4,4′,6′(1′H,3′H)-tetraone

Abstract

We describe an approach towards the synthesis of previously unknown 3-benzoyl-1′,3′,6-trimethyl-2′H,3H,4H-spiro[furo[3,2-c]pyran-2,5′-pyrimidine]-2′,4,4′,6′(1′H,3′H)-tetraone. The presented method is based on the cyclization of 5-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-2-phenylethyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione. It was shown that the presented reaction proceeds through the stage of bromination of the starting compound followed by O-nucleophilic attack. The structures of the obtained compound were established by ¹H, ¹³C NMR and IR spectroscopy, and high-resolution mass spectrometry.

1. Introduction

In organic synthesis, cyclization reactions are an effective method of producing cyclic compounds, which have a broad range of applications in fields such as materials research and drug discovery [1]. The ability to produce molecular complexity with great stereochemical control is a critical characteristic in the synthesis of different compounds and in the pharmaceutical industry. It is one of the most notable benefits of these transformations.

Barbituric acid derivatives have an extensive variety of pharmacological applications, such as anesthetics, anxiolytics, antimicrobials, antifungals, and anticancer agents [2,3]. Barbiturates present famous a medicinally privilege scaffold with wide importance in medicinal practice [4,5].

The 2-Pyrone fragment is widely spread in different natural compounds extracted from various objects of living nature and which possess different types of useful activities, among them antibiotic, neurotoxic, anti-inflammatory and cardiotonic effects [6].

Moreover, 2-pyrone is a useful starting scaffold in modern organic chemistry, as well as in the synthesis of medicines because of its special fragments, namely conjugated diene and alkoxycarbonyl group [7].

Spiro compounds are an important class of organic molecules which usually contain a fused bicyclic system with one common atom [8]. The spirocyclic fragment is also widely spread in naturally occurring compounds and medications [8].

Spirocycles have a reasonable balance between conformational rigidity and flexibility, which could lead to finding bioactive hits [9]. Spirocycles are not usual fragments in common drugs, but nowadays success in the research of the structure of the new natural compounds, as well as progress in the receiving of new spiro intermediates ensured the creation of spiro cyclic organic molecules with sufficient effects in the different fields of medicine practices as anti-tumor, anti-Alzheimer, and neuropharmacological remedies [10,11,12,13,14].

Thus, the synthesis of novel spirofurans with pyrimidine and pyrane components is a prospective area of organic chemistry.

2. Results and Discussion

We previously carried out different cyclization reactions, including the use of the N-bromosuccinimide (NBS)/sodium acetate system [15,16,17]. In these reactions, the source of the well-leaving group was molecular bromine, which was either generated during the procedure or added as a reagent.

In the present communication, we report the efficient cyclization of 5-(1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-2-phenylethyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione 1 into the previously unknown 3-benzoyl-1′,3′,6-trimethyl-2′H,3H,4H-spiro[furo[3,2-c]pyran-2,5′-pyrimidine]-2′,4,4′,6′(1′H,3′H)-tetraone 2 in ethanol at room temperature in the presence of NBS and sodium acetate for 1 h, as shown in Scheme 1.

5-(1-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-2-phenylethyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione 1 was synthesized by our research group by the interaction of phenylglyoxal hydrate, 1,3-dimethylbarbituric acid, and 4-hydroxy-6-methyl-2H-pyran-2-one (Scheme 2) [18]. The yield of compound 1 was 83%.

For this procedure, we suggest using NBS as a halogen source. N-Bromosuccinimide is a widely used and versatile reagent in organic chemistry [19]. It is simple to use, inexpensive, widely accessible, non-toxic, and more selective than bromine.

Sodium acetate is a cheap, broadly available, and non-toxic salt of acetic acid [20]. It was used as a weak base catalyst for aldol condensation of the Perkin reaction [21], for Knoevenagel condensation [22] and for the Erlenmeyer–Plöchl reaction [23].

A precipitate of the spiro[furo[3,2-c]pyran 2 is released during the reaction as it proceeds. The final point of the reaction was considered the complete discoloration of the solution (the color of the solution of the reaction mixture changed from yellow to white). Compound 2 was synthesized in an 80% yield.

The structure of new compound 2 has been confirmed using ¹H and ¹³C NMR, IR spectroscopy, mass spectrometry data, and elemental analysis. Only one set of signals was detected in the ¹H and ¹³C NMR spectra.

Taking into consideration our previous results [15,16,17], the following mechanism for the cyclization of compound 1 was proposed, as shown in Scheme 3.

The initial step of the process is the bromination of 2-oxo-2-phenylethyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione 1 using NBS with the formation of 5-bromo-5-[1-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-2-phenylethyl]-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione 3. In the presence of a base, compound 3 undergoes deprotonation, leading to the formation of intermediate A. The next intramolecular action of the hydroxy anion was on the bromo-containing carbon atom in the intermediate A resulting in spiro[furo[3,2-c]pyran-2,5′-pyrimidine] 2 formation.

3. Materials and Methods

3.1. General Methods

The solvents and reagents were purchased from commercial sources and used as received. 5-(1-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-2-phenylethyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione 1 was obtained from phenylglyoxal hydrate, 1,3-dimethylbarbituric acid, and 4-hydroxy-6-methyl-2H-pyran-2-one, according to the literature [18].

The melting point was measured with a Gallenkamp melting-point apparatus (Gallenkamp & Co., Ltd., London, UK). ¹H and ¹³C NMR spectra were recorded in DMSO-d₆ with a Bruker AM300 spectrometer (Bruker Corporation, Billerica, MA, USA) at ambient temperature. IR spectrum was registered with a Bruker ALPHA-T FT-IR spectrometer (Bruker Corporation, Billerica, MA, USA) in KBr pellets. The HRMS spectrum was obtained in electrospray ionization (ESI) mode on a Bruker MicrOTOF-Q II spectrometer (Bruker Daltonik GmbH, Bremen, Germany) and processed with Bruker Compass DataAnalysis 4.0 software. For elemental analysis, a 2400 Elemental Analyzer (Perkin Elmer Inc., Waltham, MA, USA) was used.

3.2. Synthesis of 3-Benzoyl-1′,3′,6-trimethyl-2′H,3H,4H-spiro[furo[3,2-c]pyran-2,5′-pyrimidine]-2′,4,4′,6′(1′H,3′H)-tetraone 2

5-(1-(4-Hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2-oxo-2-phenylethyl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (1) (0.398 g, 1 mmol), sodium acetate (0.082 g, 1 mmol) and N-bromosuccinimide (0.214 g, 1.2 mmol) were stirred in 5 mL EtOH for 1 h at ambient temperature. When the reaction was completed (the color of the reaction mixture became pale), the formed solid was filtered off, washed with an ice-cold EtOH–H₂O solution (1:1, 3 mL), and dried to isolate pure 3-benzoyl-1′,3′,6-trimethyl-2′H,3H,4H-spiro[furo[3,2-c]pyran-2,5′-pyrimidine]-2′,4,4′,6′(1′H,3′H)-tetraone (2).

3-Benzoyl-1′,3′,6-trimethyl-2′H,3H,4H-spiro[furo[3,2-c]pyran-2,5′-pyrimidine]-2′,4,4′,6′(1′H,3′H)-tetraone (2). White solid; yield 80% (0.317 g); mp = 210–211 °C (decomp.) (from EtOH); FTIR (KBr) cm⁻¹: 3095 (C-H Ar), 1718 (C=O), 1693 (C=O), 1648 (C-C Ar), 1597 (C-C Ar), 1217 (C-N), 1044 (C-O-C). ¹H NMR (300 MHz, DMSO-d₆): δ 2.26 (s, 3H, N-CH₃), 2.38 (s, 3H, CH₃), 3.21 (s, 3H, N-CH₃), 6.04 (s, 1H, CH), 6.70 (s, 1H, CH pyrone), 7.54 (t, ³J = 7.6 Hz, 2H, C(3)H and C(5)H Ph), 7.73 (t, ³J = 7.6 Hz, 1H, C(4)H Ph), 7.99 (d, ³J = 7.6 Hz, 2H, C(2)H and C(6)H Ph) ppm; ¹³C NMR (75 MHz, DMSO-d₆): δ 20.0 (CH₃), 27.4 (N-CH₃), 29.1 (N-CH₃), 54.7 (C(3)H), 87.7 (C(4)), 94.9 (C(3a)), 97.5 (C(7)H), 128.5 (2C, C(3)H and C(5)H Ph), 129.6 (2C, C(2)H and C(6)H Ph), 134.5 (C(4)H Ph), 135.3 (C(1) Ph), 149.6 (C(7a)), 159.5 (C(4)=O pyrim), 162.8 (C(4)=O pyrone), 164.8 (C(2)=O pyrim), 167.9 (C(6)=O pyrim), 172.2 (C(2)=O), 161.5 (C(6)-CH₃), 191.9 (C=O benzoyl) ppm; HRMS (ESI) m/z: [M + H]⁺, calcd for C₂₀H₁₇N₂O₇ 397.1030, found 397.1028; Anal. calcd. for C₂₀H₁₆N₂O₇: C, 60.61; H, 4.07; N, 7.07%; found: C, 60.65; H, 4.10; N, 7.01%.

4. Conclusions

In summary, a convenient NBS-induced cyclization for the synthesis of previously unknown 3-benzoyl-1′,3′,6-trimethyl-2′H,3H,4H-spiro[furo[3,2-c]pyran-2,5′-pyrimidine]-2′,4,4′,6′(1′H,3′H)-tetraone was elaborated. The advantages of this approach are the application of readily available starting compounds, atom economy, and easy work-up procedures, which can avoid chromatographic purification. The structure of the synthesized spiro[furo[3,2-c]pyran-2,5′-pyrimidine] was confirmed as ¹H and ¹³C NMR, and IR spectroscopy. The high-resolution mass spectrometry, and elemental analysis were also used.