4-Phenylnaphtho[2,3- c ]furan-1(3 H )-one, 9-Phenylnaphtho[2,3- c ]furan-1(3 H )-one and 3 a ,4-Dihydro-9-phenylnaphtho[2,3- c ]furan-1(3 H )-one Crystal Structures

: The crystal structures are reported for two unsubstituted arylnaphthalene lactones, 4-phenylnaphtho[2,3- c ]furan-1(3 H )-one (2), 9-phenylnaphtho[2,3- c ]furan-1(3 H )-one (3) and a non-aromatic dihydro arylnaphthene lactone, 3 a ,4-dihydro-9-phenylnaphtho[2,3- c ]furan-1(3 H )-one (5). There are only minor differences in the geometrical parameters of these structures. However, in certain cases, both isomers of arylnaphthalene lactones (termed Type I and Type II) were found in the same asymmetric unit cell. the reaction (Scheme 1). Additionally, both Type I and Type II were found to co-crystallize in the same asymmetric cell unit: an interesting crystal structure with two different isomers with different properties such as melting point and polarity.


Introduction
Arylnaphtalene lactones are a subclass of lignans that can be extracted from a wide range of species such as Justicia [1]. These derivatives, due to their wide variety of biological activities such as antifungal [2], antileishmanial [2], antiviral [3,4] and anti-inflammatory [5] are now widely studied as potential therapeutic leads. Several arylnaphtalene lactones have been extracted from a variety of plants and are divided into two types (Type I and Type II) corresponding to the position of the lactone on the molecular system [6,7]. Furthermore, for the past two decades, many pathways for the synthesis of these molecules and their numerous scaffolds' assembly have been investigated in order to further study their bioactivities [8][9][10][11][12][13][14][15].
Of the many synthetic routes explored to efficiently obtain these arylnapthalene lactones, intramolecular Diels-Alder methods [8], multicomponent methods [9], Suzuki cross-coupling reactions [10], oxidative cyclizations [11], silver-catalyzed one-pot synthesis [12] and metal-catalyzed annulations [13][14][15] are just a sample of the possible synthetic pathways available. Each of these approaches allow access to a large variety of original lactones, bearing a variety of substituents along the conjugated backbone.
For many arylnapthalene lactones, isolated or synthesized, several crystal structures have been published. However, to our knowledge, no crystal structures of their bare scaffolds have been investigated. Such a structural investigation is an essential element for a better understanding of the structure-property relationship and the bioactivities associated with these lignans. Furthermore, these crystal structures could provide the insight necessary to implement further modification to their conjugated backbones without interfering with their overall structural scaffolds.
In this communication, we focused on the heat-mediated Dehydro-Diels-Alder synthetic approach to these arylnaphthalene lactones [16][17][18]. This approach not only yielded both arylnaphthalene lactone types (Type I and II) in good yields and purity, but interestingly showed a dramatic solvent effect. Indeed, when the solvent was switched from toluene to ethanol, a partially aromatic arylnaphthalene lactone was the main product of reaction (Scheme 1). Additionally, both Type I and Type II were found to co-crystallize in the same asymmetric cell unit: an interesting crystal structure with two different isomers with different properties such as melting point and polarity. Scheme 1. Synthesis of lactones 2, 3 and 5.

Materials and Instrumentation
All reagents and solvents were purchased from Sigma-Aldrich and used without further purification. All NMR spectra were recorded on a Bruker Avance III 400 MHz or a Bruker Avance III 500 MHz spectrometer and were referenced to the residual chloroform (CDCl3) resonance at 7.26 ppm for proton and 77.16 ppm for carbon. All cyclization reactions were performed on a 6 mL scale using toluene or ethanol as a solvent in an Anton Parr Monowave 50 reactor at 140 °C in a 10 mL capped vial fitted with a magnetic stir bar. All chromatography separations were performed on a Teledyne Combiflash system using silica gel disposable flash columns (RediSep Rf, normal phase, 40-60 micron) and ethyl acetate/hexanes mixtures as eluent. All TLC analyses were performed on aluminum backed plates pre-coated with silica gel (Merck, Silica Gel 60 F254) and visualized by UV light.

Synthesis
2.1.1. Synthesis of 3-Phenylprop-2-yn-1-yl 3-phenylpropiolate (1) and Trans-cinnamyl 3phenylpropiolate (4) General method: tthe acid (2.05 mmol, 1 equiv.) and 4-dimethylaminopyridine (0.15 mmol, 0.07 equiv.), solution of cinnamyl alcohol (1.85 mmol, 0.9 equiv.) in dichloromethane (DCM, 10 mL) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI, 2.46 mmol, 1.2 equiv.) were added to a flame-dried 5 mL two-necked round-bottom flask that was equipped with an argon inlet adapter, a septum and a stir bar. The reaction mixture was stirred at room temperature for 3 h and diluted with DCM (15 mL) followed by filtration through a plug of silica gel. The crude material was subsequently concentrated under reduced pressure to yield the desired ester. When the NMR showed traces of either the starting material or a coupling agent, the crude was simply dissolved in DCM (10 mL) and filtered one more time through another silica gel plug. This second filtration yielded high grade material suitable for subsequent steps without further purification.

Materials and Instrumentation
All reagents and solvents were purchased from Sigma-Aldrich and used without further purification. All NMR spectra were recorded on a Bruker Avance III 400 MHz or a Bruker Avance III 500 MHz spectrometer and were referenced to the residual chloroform (CDCl 3 ) resonance at 7.26 ppm for proton and 77.16 ppm for carbon. All cyclization reactions were performed on a 6 mL scale using toluene or ethanol as a solvent in an Anton Parr Monowave 50 reactor at 140 • C in a 10 mL capped vial fitted with a magnetic stir bar. All chromatography separations were performed on a Teledyne Combiflash system using silica gel disposable flash columns (RediSep Rf, normal phase, 40-60 micron) and ethyl acetate/hexanes mixtures as eluent. All TLC analyses were performed on aluminum backed plates pre-coated with silica gel (Merck, Silica Gel 60 F254) and visualized by UV light.

Synthesis of 3-Phenylprop-2-yn-1-yl 3-phenylpropiolate (1) and Trans-cinnamyl 3-phenylpropiolate (4)
General method: tthe acid (2.05 mmol, 1 equiv.) and 4-dimethylaminopyridine (0.15 mmol, 0.07 equiv.), solution of cinnamyl alcohol (1.85 mmol, 0.9 equiv.) in dichloromethane (DCM, 10 mL) and N-(3-Dimethylaminopropyl)-N -ethylcarbodiimide hydrochloride (EDCI, 2.46 mmol, 1.2 equiv.) were added to a flame-dried 5 mL two-necked round-bottom flask that was equipped with an argon inlet adapter, a septum and a stir bar. The reaction mixture was stirred at room temperature for 3 h and diluted with DCM (15 mL) followed by filtration through a plug of silica gel. The crude material was subsequently concentrated under reduced pressure to yield the desired ester. When the NMR showed traces of either the starting material or a coupling agent, the crude was simply dissolved in DCM (10 mL) and filtered one more time through another silica gel plug. This second filtration yielded high grade material suitable for subsequent steps without further purification.

X-ray Analysis
X-ray Crystallography: suitable crystals were coated in paratone oil and mounted on a MiTeGen Micro Mount. All the relevant data were collected on a Bruker Smart instrument equipped with a Photon II CCD area detector fixed at a distance of 5.0 cm from the crystal and a Mo Kα fine focus sealed tube (λ = 0.71073 nm) operated at 1.5 kW (50 kV, 30 mA), filtered with a graphite monochromator.
Data were collected and integrated using the Bruker SAINT software package [18] and were corrected for absorption effects using the multi-scan technique (SADABS) [19] or (TWINABS) [20,21]. All structures were solved by direct methods [22,23]. All nonhydrogen atoms were refined anisotropically. All hydrogen atoms were placed in calculated positions with isotropic refines and U values 1.2 times greater than the U(eq) value of the corresponding non-hydrogen atom. All refinements were performed using the SHELXTL crystallographic software package of Bruker-AXS [24]. The molecular drawings were generated by the use of POV-RAY [25]. The mixture 2,3 crystallized with two isomers in the asymmetric unit and was modeled in two orientations (44 and 56%). Additional crystallographic information can be found in Table 1.

Results
The crystal structures of 2, 3, mixture 2-3 and 5 were determined by single-crystal X-ray diffraction and are shown in Figure 1 along with the atomic numbering schemes. In the mixture 2-3, both cis and trans isomers of arylnaphthalene lactones (Type I and Type II, respectively) were found in the same asymmetric unit cell, and they were molded in two orientations as cis isomers (O3 57.7%) and trans isomers (O2 42.3%). These unique co-crystallized isomers are stabilized by hydrogen bond interactions between O3-H14, O3-H16 and O2-H1, O2-H2 (shown in Figure S6). For all structures, the torsion angles ( • ) between the phenyl group and the naphthoquinone moiety are shown in Figure 2 and were found to be 62.43 and 62.85 • in structure 3 and the mixture 2-3, respectively. On the other hand, the large torsion angle of 68.12 • in structure 2 may have been due to less steric hindrance of the trans ketone group. For compound 5, an intermediate species in the reaction, however, the presence of an sp 3 hybridized carbon C8 in the lactone did not allow for the measurement of the torsion angle due to the non-planarity and non-aromaticity of the structure.  Compound 5 has two sp 3 hydrogens on the lactone and can be fully aromatized to compound 3 when heated at higher temperatures in the presence of Pd/C. A similar structure was published by Amer et al. [26] with the only difference being the double-bond position in the cyclohexene ring [26]. A different symmetry of packing found in that case was also consistent with the published space group [26]. The structures of 2, 3 and mixture 2-3 have an isostructural unit cell (monoclinic P21/c), while the structure of 5 has a monoclinic P21/n unit cell. Packing views along the a-axis are also shown in Figure 4 for all the structures. In the unit cell packing, four independent structures were placed in the asymmetric unit in a volume of approximately 1300 Å 3 . Compound 5 has two sp 3 hydrogens on the lactone and can be fully aromatized to compound 3 when heated at higher temperatures in the presence of Pd/C. A similar structure was published by Amer et al. [26] with the only difference being the double-bond position in the cyclohexene ring [26]. A different symmetry of packing found in that case was also consistent with the published space group [26]. The structures of 2, 3 and mixture 2-3 have an isostructural unit cell (monoclinic P2 1 /c), while the structure of 5 has a monoclinic P2 1 /n unit cell. Packing views along the a-axis are also shown in Figure 4 for all the structures. In the unit cell packing, four independent structures were placed in the asymmetric unit in a volume of approximately 1300 Å 3 .

Conclusions
The investigation of a Dehydro-Diels-Alder synthetic method for the synthesis of arylnapthalene lactones led to a set of high yield crystalline products. Four crystal structures of arylnapthalene lactones' bare scaffolds were collected and discussed in this communication. This method provided us with a set of fully characterized X-ray structures of arylnaphthalene lactones 2 and 3, a partially aromatic intermediate 5, as well as a unique

Conclusions
The investigation of a Dehydro-Diels-Alder synthetic method for the synthesis of arylnapthalene lactones led to a set of high yield crystalline products. Four crystal structures of arylnapthalene lactones' bare scaffolds were collected and discussed in this communication. This method provided us with a set of fully characterized X-ray structures of arylnaphthalene lactones 2 and 3, a partially aromatic intermediate 5, as well as a unique mix-isomer structure (mixture 2-3). This mixture containing both arylnapthalene lactones isomers of Type I and Type II in the crystal is an interesting find and could further help with the bioactivity and therapeutic studies of these compounds. CCDC 2,092,032 (2), 2,092,033 (3), 2,092,034 (mixture 2-3) and 2,092,035 (5) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre.