CHEN Chao-Yue HU Jin-Song CHAI Fei-Fei XIE Kai-Yun ZHANG Xiao-Mei SHI Jian-Jun

(School of Chemical Engineering, Anhui University of Science and Technology, Huainan, Anhui 232001, China)

1 INTRODUCTION

6H-Dibenzo[b,d]pyran-6-ones, also known as biaryl lactones, represent a structurally diverse group of coumarin derivatives which contain a fused tricyclic nucleus, including families of urolithins[1-4],graphislactones[5-8], gilvocarcins[9-13], defuco-gilvocarcins[10,14]and chrysomycins[7,12-14](Fig. 1). They are usually isolated from plant and animal sources and are metabolic products of microorganisms[1-14].Many of them exhibit a wide range of biological activities, including antioxidant, antibacterial, antibiotic, anticancer, antiallergic, and immunomodulating effects[1-14]. In addition, 6H-dibenzo[b,d]pyran-6-ones are the key intermediates used for the preparation of cannibinol/cannabinoids and other related natural products[12,15].

With this background and in continuation of our research in search of new 6H-dibenzo[b,d]pyran-6-ones with potential pharmaceutical value, we synthesized ethyl 3,9-dimethyl-7-phenyl-6H-dibenzo-[b,d]pyran-6- one-8-carboxylate starting from cheap and easily available raw materials, such as ethyl acetoacetate, benzaldehyde, and 3-methyl-phenol.The structure of the target compound was determined by1H and13C NMR, ESI-MS, elemental analysis, and X-ray single-crystal diffraction.

2 EXPERIMENTAL

2.1 Reagents and instruments

All reagents were obtained from commercial suppliers and used without further purification. The1H NMR and13C NMR spectra were recorded on Bruker ARX-300 (300 MHz) or Bruker Avance 400(400 MHz) NMR spectrometer. MS (ESI) spectra were obtained on a Finnigan-Mat LCQ mass spectrometer. Elemental analysis was carried out on an Elementar Vario MICRO CUBE (German). Fluorescence spectra were obtained from an RF-5301PC spectrometer. Thermogravimetry (TG) was recorded on a Perkin-Elmer thermal analyzer at a heating rate of 10 ℃/min. Melting points were determined on an electrically heated RK-Z melting point apparatus(Analytical Instrument Factory in Tianjin, China)and were uncorrected.

2.2 Synthesis of the compound

The synthetic procedure for the title compound is shown in Scheme 1.

Scheme 1. Synthetic procedure of the title compound

Diethyl 4-hydroxy-4-methyl-6-oxo-2-phenyl-cyclohexane-1,3-dicarboxylate (1) was synthesized according to the method reported by Pandiarajan and coworkers[16]except that piperidine was used instead of methylamine: A mixture of ethyl acetoacetate(2.66 g, 20.4 mmol), benzaldehyde (1.06 g, 10 mmol)and piperidine (0.4 mL) in ethanol (20 mL) was stirred at room temperature for about 12 h. The precipitate formed was filtered and purified by recrystallization from ethanol. White solid; Yield:84%; m.p: 153～155 ℃ (lit.[16]. 156 ℃).1H NMR(300 MHz, CDCl3) δ (ppm): 7.28～7.22 (m, 5H),4.08～3.95 (m, 3H), 3.91～3.79 (m, 2H), 3.69 (d, J= 12.6 Hz, 1H), 3.04 (d, J = 12.0 Hz, 1H), 2.71 (d, J= 14.4 Hz, 1H), 2.51 (d, J = 14.4 Hz, 1H), 1.34 (s,3H), 1.03 (t, J = 7.2 Hz, 3H), 0.79 (t, J = 7.2 Hz, 3H).

A mixture consisting of 0.89 g (8.2 mmol) of 3-methylphenol, 2.79 g (8.0 mmol) of diethyl 4-hydroxy-4-methyl-6-oxo-2-phenylcyclohexane-1,3-dicarboxylate (1), 25 mL of TFA and 1.0 mL of MSA was refluxed for 40 h. After completion of the reaction, TFA in the reaction mixture was evaporated in vacuo with a rotary evaporator. The residue was diluted with ethyl acetate (50 mL), then washed with saturated NaHCO3solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice (2 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel,EtOAc:hexane = 1:1 as eluent) to afford ethyl 7,8-dihydro-3,9-dimethyl-7-phenyl-6H-dibenzo[b,d]py ran-6-one-8-carboxylate (2). Yellow solid. Yield:55%; m.p: 185～187 ℃. Anal. Calcd. (%) for C24H22O4: C, 76.99; H, 5.92. Found (%): C, 76.87; H,5.88.1H NMR (300 MHz, CDCl3) δ (ppm): 7.67 (d,J = 8.7 Hz, 1H), 7.29～7.20 (m, 5H), 7.15～7.12 (m,2H), 6.85 (d, J = 1.2 Hz, 1H), 4.81 (s, 1H), 4.16 (q, J= 7.2 Hz, 2H), 3.41 (s, 1H), 2.45 (s, 3H), 2.09 (d, J =1.2 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H).13C NMR (75 MHz, CDCl3) δ (ppm): 170.7, 161.2, 153.6, 143.4,142.2, 141.3, 140.9, 128.7, 127.28, 127.25, 125.3,123.4, 117.8, 117.4, 116.9, 114.9, 61.5, 52.4, 39.7,24.7, 21.6, 14.1. MS (ESI) m/z [M+H]+Calcd. for C24H23O4: 375.16; found: 375.15.

A solution of compound 2 (0.374 g, 1.0 mmol) in anhydrous CH3CN was cooled to 0 ℃ with stirring under nitrogen, and distilled DBU (0.167 g, 1.1 mmol) was added. Bromotrichloromethane (0.218 g,1.1 mmol) was then introduced dropwise via syringe over 10 min. The reaction mixtures were allowed to warm to room temperature and stirred until the starting material was completely consumed (monitored by TLC). The mixture was neutralized with TFA (1.1 equiv.), and the solvent was evaporated in vacuo with a rotary evaporator. The residue was purified by flash chromatography, providing ethyl-3,9-dimethyl-7-phenyl-6H-dibenzo-[b,d]pyran-6-one-8-carboxylate (3) in 73% yield. White solid; m.p:181～184 ℃. Anal. Calcd. (%) for C24H20O4: C,77.40; H, 5.41. Found (%): C, 77.29; H, 5.36.1H NMR (400 MHz, CDCl3) δ (ppm): 7.96 (s, 1H), 7.94(d, J = 8.0 Hz, 1H), 7.40～7.37 (m, 3H), 7.26～7.23(m, 2H), 7.13 (d, J = 8.0 Hz, 1H), 7.10 (s, 1H), 3.95(q, J = 8.0 Hz, 2H), 2.52 (s, 3H), 2.43 (s, 3H), 0.93 (t,J = 8.0 Hz, 3H).13C NMR (125 MHz, CDCl3) δ(ppm): 168.1, 158.8, 151.8, 143.6, 141.8, 141.1,138.9, 136.9, 136.5, 128.3, 127.5, 127.4, 125.4,122.9, 122.4, 117.6, 116.6, 114.8, 61.3, 21.4, 20.4,13.7. MS (ESI) m/z [M+H]+Calcd. for C24H21O4:373.14; found: 373.10.

2.3 Structure determination

A colorless single crystal (0.20mm × 0.20mm ×0.20mm) of the title compound was selected and mounted on the top of a glass fibre. The data were collected on a Bruker Apperx II diffractometer equipped with a graphite-monochromatic MoKα radiation (λ = 0.71073 ?) using an oscillation frames scan mode at 296(2) K. A total of 7831 reflections were collected in the range of 5.59＜θ＜25.00o by using a ψ-ω scan mode with 3259 independent ones(Rint= 0.023), of which 2916 with I ＞ 2σ(I) were observed and used in the succeeding refinements.The unit cell dimensions were obtained with the least-squares refinements. The structure was solved by direct methods with SHELXS-97 program[17]and refined by full-matrix least-squares method on F2with anisotropic thermal parameters for all nonhydrogen atoms using SHELXL-97[18]. The final refinement gave R = 0.0482, wR = 0.1281 (w =1/[σ2(Fo2) + (0.1000P)2+ 0.0000P], where P = (Fo2+ 2Fc2)/3), (Δ/σ)max= 0.000, (Δ/ρ)max= 0.039 and(Δ/ρ)min= –0.167 e/?3. The non-hydrogen atoms were refined anisotropically, and hydrogen atoms were added according to theoretical models. Molecular illustrations were prepared using the XP package.

Fig. 1. Some natural products possessing 6H-dibenzo[b,d]pyran-6-one core structure

3 RESULTS AND DISCUSSION

3.1 Structural description

Firstly, diethyl 4-hydroxy-4-methyl-6-oxo-2-phenylcyclohexane-1,3-dicarboxylate (1) was prepared in excellent yield by condensing benzaldehyde with ethyl acetoacetate under the catalysis of piperidine.Compound 1 then reacted with 3-methylphenol in the presence of TFA-MSA, giving 2. Dehydroge-nation of compound 2 performs expediently with DBU-CBrCl3, furnishing desired 3 in 73% yield.The1H NMR spectrum of compound 3 showed two singlets at δ 7.96 (s, 1H) and 7.10 (s, 1H) due to the aromatic protons of H-10 (Fig. 1) and H-4, respectively. Two doublets at δ 7.94 (d, J = 8.0 Hz, 1H)and 7.13 (d, J = 8.0 Hz, 1H) are observed for H-1 and H-2, respectively. Multiple peaks δ from 7.40 to 7.37 (m, 3H) and 7.26 to 7.23 (m, 2H) are corresponding to the protons of the phenyl group attached at C-7. Peaks at δ 2.52 (s, 3H) and 2.43 (s, 3H)are assigned respectively to the protons of two methyl groups attached to C-3 and C-9. Ethyl group presenting as the side chain showed a triplet at δ 0.93 (t, J = 8.0 Hz, 3H) and a quartet at δ 3.95 (q, J= 8.0 Hz, 2H). The13C NMR spectrum of compound 3 displayed 22 carbon signals, consisting of two carbonyl carbon signals, sixteen sp2-hybridized aromatic carbon signals, one oxygenated methylene signal, and three methyl carbon signals. Mass spectrum (ESI) of compound 3 exhibited a pseudomolecular ion peak [M+H]+at m/z 373.10.Elemental analytical data of compound 3 (in accordance with the calculated values) were within±0.4% of theoretical values.

3.2 Crystal structure analysis

The molecular structure of the title compound is depicted in Fig. 2, and the selected bond lengths and bond angles are given in Table 1. Generally, the average bond lengths and bond angles of the tricyclic ring systems fall in the normal ranges. The fused phenyl ring A (C(4)–C(9)–C(13)–C(20)–C(19)–C(14)) and lactone ring B (C(1)–C(2)–C(4)–C(9)–O(3)–C(10)) are planar and the dihedral angle between them is 4.212o, thus making the coumarin moiety nearly planar. Another phenyl ring C (C(1)–C(2)–C(7)–C(8)–C(5)–C(3)) which is annulated to the coumarin is somewhat out of the plane of pyrone ring, making a dihedral angle of 8.760o. A much more detailed analysis shows that the distance between the two hydrogen atoms respectively attached at C(7) and C(14) is 2.165 ?, which is shorter than the sum of the van der Waals radii of two hydrogen atoms (2.4 ?)[19–20], indicating a steric interaction between them. As a result of this interaction, the phenyl ring C displays distortion out of the plane of the lactone ring B connected to it.Only in this way can the steric hindrance caused by the two hydrogen atoms be reduced. This explanation is corroborated by the fact that the angles of C(14)–C(4)–C(2) and C(7)–C(2)–C(4) are increased to 124.26(16)o and 122.67(14)o, respectively. The third phenyl ring (C(6)–C(12)–C(17)–C(18)–C(16)–C(15)) attached at C(3) is twisted dramatically out of the plane of the benzene ring to which it is connected (dihedral angle of 60.974o). This is attributed to the steric hindrance caused by these two phenyl rings. A dramatic twisting is also observed between the phenyl ring C and the ester carboxylate group which attached to it, with the dihedral angle between them being 78.307o. This result is distinct from that in the benzoic acid esters in which the ester carboxylate groups are normally found to be essentially coplanar with phenyl rings. This kind of arrangement can ease the steric hindrance caused by the bulky phenyl and methyl groups, and also facilitates the electrostatic interaction.

In addition, aromatic π-π stacking interactions are observed between the fused tricyclic rings of neighboring molecules in a head-to-tail fashion. It is striking that in a perpendicular sense to the layers,lactone ring B is overlapped with the next molecules’ lactone ring B with a plane-to-plane separation of 3.847 ?, while phenyl ring A overlaps with the phenyl ring C and vice versa (centroid to centroid distance = 3.781 ?). This kind of packing can achieve a maximum overlap of the π-electron systems. Obviously, the π-π stacking interactions reinforce the structural stability and favor the construction of a stable dimer of compound 3.

3.3 Thermal properties of compound 3

The thermal stability of 3 was examined by the thermogravimetric analyses (TGA) under nitrogen atmosphere at a heating rate of 10 ℃·min-1from 45 to 600 ℃ . TG curve (Fig. 3) of 3 reveals a single weight loss event approximately beginning at 308 ℃and ending at 387 ℃. The “to start weight loss temperature” indicates that 3 enjoys the fairly high thermal stability below 308 ℃.

3.4 Photophysical properties of compound 3

Many 6H-dibenzo[b,d]pyran-6-ones exhibit a wide range of fluorescence emission properties[21].Fluorescence spectra of 3 (Fig. 4) present an emission band at 450 nm when excited with 380 nm radiation at room temperature in CH3CN. Meanwhile, it exhibits relatively narrower half peak breadth due to the rigid structure and big conjugate system of biaryl lactone.

Table 1. Selected Bond Lengths (?) and Bond Angles (°) for the Title Compound

Fig. 2. (a) ORTEP drawing of compound 3. (b) View of the π-π stacking interactions of adjacent molecules

Fig. 3. TG curve of compound 3

Fig. 4. Fluorescence spectra of compound 3 in CH3CN

4 CONCLUSION

In summary, the biaryl lactone derivative, ethyl 3,9-dimethyl-7-phenyl-6H-dibenzo[b,d]pyran-6-one-8-carboxylate, has been synthesized and characterized by1H and13C NMR, ESI-MS, and elemental analysis. The single crystal was cultivated and analyzed by single-crystal X-ray diffraction. In the crystal structure, the fused tricyclic nucleus of the title compound is not fully coplanar. Analysis of the crystal packing indicates aromatic π-π stacking interactions occurring between the fused tricyclic aromatic rings of neighboring molecules in which a maximum overlap of the π-electron systems was achieved. The thermal stability of the title compound has been studied, and most weight was lost when the temperature ranged from 308 to 387 ℃. Fluorescence spectra analysis shows that it emits blue fluorescence at 450 nm under 380 nm excitation with a narrow half peak breadth, so it can be used as a potential photo-luminescence material.

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