Synthesis of structurally diverse 3,4-dihydropyrimidin-2(1H)-ones via sequential Biginelli and Passerini reactions

The Biginelli reaction was combined with the Passerini reaction for the first time in a sequential multicomponent tandem reaction approach. After evaluation of all possible linker components and a suitable solvent system, highly functionalized dihydropyrimidone–α-acyloxycarboxamide compounds were obtained in good to excellent yields. In a first reaction step, different 3,4-dihydropyrimidin-2(1H)-one acids were synthesized, isolated and fully characterized. These products were subsequently used in a Passerini reaction utilizing a dichloromethane/dimethyl sulfoxide solvent mixture. By variation of the components in both multicomponent reactions, a large number of structurally diverse compounds could be synthesized. In addition, a one-pot Biginelli–Passerini tandem reaction was demonstrated. All products were carefully characterized via 1D and 2D NMR as well as IR and HRMS.


1
H and 13 C NMR spectra were recorded on Bruker Avance DPX spectrometers (Billerica, MA) with a 5 mm dual proton/carbon probe (300 and 400 MHz), on a Bruker Avance III with a 5 mm z-gradient cryogenically cooled probe head (CPTCI, 600 MHz 1 H/75.5 MHz) or on a 500 MHz WB Bruker Avance I spectrometer with a proton frequency of 499.97 MHz, 13 C frequency of 125.72 MHz on a 8 mm TXI probe head with actively shielded z-gradients (at Θ = 0°) and on a 4 mm triple HCX MAS probe head (at ca. Θ = 65°) at 298 K, regulated with a Bruker VTU-3000. Unless otherwise stated, all spectra were measured at ambient temperature. The chemical shift for 1 H NMR spectra are reported in parts per million (ppm) referenced to characteristic solvent signals of partly deuterated solvents, e.g., CDCl 3 at 7.26 ppm or the centroid peak of the DMSO-d 6 quintet at 2.50 ppm. 13 C NMR spectra are reported in ppm relative to characteristic signals of partly deuterated solvents, e.g., the centroid peak of the CDCl 3 triplet at 77.00 ppm or the DMSO-d 6 septet at 39.52 ppm.
Fast-atom-bombardment (FAB) and electron ionization (EI) spectra were recorded utilizing a Finnigan MAT 95 mass spectrometer. Infrared spectra (IR) were recorded on a Bruker Alpha-p instrument applying ATR-technology. S4 General Procedure (GP 1) for Biginelli reactions. In a flask of appropriate size, finely powdered urea (1.20 equiv) was mixed with the aldehyde (1.00 equiv) and suspended in a small amount dimethyl sulfoxide (1.50-3.00 M for 1.00 equiv). Subsequently, the acetoacetate (1.20 equiv) and 4-methylbenzenesulfonic acid (p-TSA, 0.10 equiv) were added. The resulting suspension was stirred at 110 °C for 4-8 h and subsequently for 2-4 d at 80 °C until TLC in ethyl acetate/c-hexane indicated complete conversion of the aldehyde. Subsequently, the crude reaction mixture was added dropwise into 100 mL of water while stirring; the resulting slurry was stirred for several hours until a precipitate was formed. The precipitate was filtered off, crushed, washed three times with water, dried and washed three times with cold nhexane/ethyl acetate (2:1). The product was dried under reduced pressure.
General Procedure (GP 2) for Passerini reactions. In a flask of appropriate size, finely powdered Biginelli acid (1.00 equiv) was suspended in dichloromethane and dimethyl sulfoxide was slowly added dropwise while stirring until the compound was completely dissolved.
Subsequently, the aldehyde (1.50 equiv) was added and stirred for a few minutes at room temperature. Afterwards, the isocyanide (1.50 equiv) was added to the mixture. The reaction was stirred at room temperature for 3-5 d. TLC in ethanol indicated complete conversion of the Biginelli acid. The crude reaction mixture was dried under reduced pressure and purified via column chromatography on silica gel eluting with a gradual solvent mixture of c-hexane/ethyl acetate or c-hexane/diethyl ether. S5 Figure S1: Overview: Synthesized DHMP acids 13-18 and Biginelli-Passerini products 19-27.
The suspension was stirred for 3 h until a precipitate was formed. The precipitate was filtered off, crushed, washed with water (3 x 30 mL) and dried. Then, the precipitate was washed with and n-hexane (2 x 30 mL) and dried under reduced pressure to yield the Biginelli product 13 as a pale yellow solid (4.86 g, 15.1 mmol, 90.5%).  Spectral data is in accordance to those reported by Arab-Ameri et al. [2] S7 S8 S9 Biginelli acid 14 derived from Biginelli-benzyl ester 13 In a tube vial equipped with a magnetic stir bar, the Biginelli-benzyl ester 13 (800 mg, 2.48 mmol, 1.00 equiv) was dissolved in 8.00 mL acetic acid/ethanol (1:3). Subsequently, palladium on activated charcoal (10 wt % Pd, 80.0 mg) was added to the solution and the vial was placed inside an autoclave. Hydrogen gas (20 bar) was applied and the reaction was stirred for 15 h at 50 °C. The crude reaction mixture was concentrated under reduced pressure and stirred with 10 mL 1 M sodium hydroxide solution for 20 min. The suspension was filtered and the yellow filtrate was acidified with hydrochloric acid (pH 1). The white precipitate was filtered off, washed with water (2 × 30 mL), diethyl ether (3 × 50 mL) and was subsequently dried under reduced pressure: The Biginelli acid 14 was obtained as a colorless solid (533 mg, 2.29 mmol, 92.5%).  H NMR data is in accordance to those reported by Kappe et al. [3] S10 S11 S12   NMR Spectral data is in accordance to those reported by Ryabukhin et al. [4] S13 S14 S15     NMR Spectral data is in accordance to those reported by Fernandes et al. [5] S20 S21 Biginelli acid 18 derived from 4-formylbenzoic acid, urea and benzyl acetoacetate In a 25 mL round-bottomed flask, finely powdered urea (1.50 g, 24.9 mmol, 1.50 equiv) and
The reaction mixture was evaporated under reduced pressure. The crude product was purified via column chromatography employing silica gel and eluting with a gradual solvent mixture of ethyl acetate and c-hexane (0:1  1:1) and finally with a solvent mixture of dichloromethane,