3.1.3. Synthesis of 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxy-4H-chromen-4-one (5)

**Figure 1.** (**A**) Molecular structure of the title compound **5** with atomic labelling. The asymmetric part of the unit cell incorporates two independent molecules **5I** (C1–C19) and **5II** (C20–C38). Displacement The previously reported literature procedures were used but starting with the 3-iodo flavone compound (**3**) [34,45]. For the complete assignment for the proton atoms and carbon atoms, additional two-dimensional NMR such as HMBC (heteronuclear multiple bond correlation), HMQC (heteronuclear multiple-quantum correlation) and TOCSY (total correlation spectroscopy) were performed (Supplementary Materials). <sup>1</sup>H NMR (400 MHz, DMSO-*d6*) δ 8.34 (s, 1H, H-2), 7.47 (s, 1H, H-5), 7.16 (s, 1H, H-8), 7.15 (d, 1H, H-2<sup>0</sup> , *J* = 2.1 Hz), 7.06 (dd, 1H, H-6<sup>0</sup> , *J* = 8.4, 2.1 Hz), 6.88 (d, 1H, H-5<sup>0</sup> , *J* = 8.4 Hz), 4.27 (s, 4H, 3<sup>0</sup> , 40 -CH2), 3.93 (s, 3H, 7-OCH3), 3.88 (s, 3H, 6-OCH3); <sup>13</sup>C NMR (400 MHz, DMSO-*d6*) <sup>δ</sup> 173.9 (C-4), 154.2 (C-7), 152.8 (C-2), 151.5 (C-9), 147.4 (C-6), 143.0 (C-4<sup>0</sup> ), 142.8 (C-3<sup>0</sup> ), 124.9 (C-1<sup>0</sup> ), 122.4 (C-3), 121.5 (C-6<sup>0</sup> ), 117.3 (C-2<sup>0</sup> ), 117.0 (C-10), 116.4 (C-5<sup>0</sup> ), 104.4 (C-5), 100.1 (C-8), 63.90 (C-3<sup>0</sup> ), 63.86 (C-4<sup>0</sup> ), 56.1 (7-OCH3), 55.7 (6-OCH3). HR/MS (m/z): Calcd. for (M+H)+: 341.0980; Found: 341.1032.

#### ellipsoids are drawn at the 30% probability level. The minor component of the disordered moiety is *3.2. Crystal Structure of Isoflavone Compound 5*

The asymmetric unit of compound **5** consists of two independent molecules **5I** (C1–C19) and **5II** (C20–C38). In each independent molecules, two methylene groups C18–C19 (**5I**) and C37–C38 (**5II**) in corresponding 1, 4-dioxane rings are disordered over two positions with relative occupancies of 0.599(10) (**5I**) and 0.812(9) (**5II**) for the major component **A**, and 0.401(10) (**5I**) and 0.188(9) (**5II**) for the minor component **B**, respectively (Figure 1A). From a macroscopic point of view, two independent molecules **5I** and **5II** are roughly superimposed over each other as shown in Figure 1B.

independent molecules **5I** and **5II** are roughly superimposed over each other as shown in Figure 1B.

**Scheme 1.** Synthetic procedures for the title compound **5**.

The asymmetric unit of compound **5** consists of two independent molecules **5I** (C1–C19) and **5II**  (C20–C38). In each independent molecules, two methylene groups C18–C19 (**5I**) and C37–C38 (**5II**) in corresponding 1, 4-dioxane rings are disordered over two positions with relative occupancies of

3.3.3. Synthesis of 3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxy-4H-chromen-4-one (5)

OCH3), 55.7 (6-OCH3). HR/MS (m/z): Calcd. for (M+H)<sup>+</sup>

*3.2. Crystal Structure of Isoflavone Compound 5*

The previously reported literature procedures were used but starting with the 3-iodo flavone compound (**3**) [34,45]. For the complete assignment for the proton atoms and carbon atoms, additional two-dimensional NMR such as HMBC (heteronuclear multiple bond correlation), HMQC (heteronuclear multiple-quantum correlation) and TOCSY (total correlation spectroscopy) were performed. <sup>1</sup>H NMR (400 MHz, DMSO-*d6*) δ 8.34 (s, 1H, H-2), 7.47 (s, 1H, H-5), 7.16 (s, 1H, H-8), 7.15 (d, 1H, H-2′, *J* = 2.1 Hz), 7.06 (dd, 1H, H-6′, *J* = 8.4, 2.1 Hz), 6.88 (d, 1H, H-5′, *J* = 8.4 Hz), 4.27 (s, 4H, 3′, 4′-CH2), 3.93 (s, 3H, 7-OCH3), 3.88 (s, 3H, 6-OCH3); 13C NMR (400 MHz, DMSO-*d6*) δ 173.9 (C-4), 154.2 (C-7), 152.8 (C-2), 151.5 (C-9), 147.4 (C-6), 143.0 (C-4′), 142.8 (C-3′), 124.9 (C-1′), 122.4 (C-3), 121.5 (C-6′), 117.3 (C-2′), 117.0 (C-10), 116.4 (C-5′), 104.4 (C-5), 100.1 (C-8), 63.90 (C-3′), 63.86 (C-4′), 56.1 (7-

: 341.0980; Found: 341.1032.

**Figure 1.** (**A**) Molecular structure of the title compound **5** with atomic labelling. The asymmetric part of the unit cell incorporates two independent molecules **5I** (C1–C19) and **5II** (C20–C38). Displacement ellipsoids are drawn at the 30% probability level. The minor component of the disordered moiety is **Figure 1.** (**A**) Molecular structure of the title compound **5** with atomic labelling. The asymmetric part of the unit cell incorporates two independent molecules **5I** (C1–C19) and **5II** (C20–C38). Displacement ellipsoids are drawn at the 30% probability level. The minor component of the disordered moiety is drawn with open bonds. (**B**) An overlay diagram of two independent crystals **5I** (orange color) and **5II** (blue color) of title compound **5**. H atoms are omitted for clarity. *Crystals* **2020**, *10*, x FOR PEER REVIEW 6 of 15 drawn with open bonds. (**B**) An overlay diagram of two independent crystals **5I** (orange color) and **5II** (blue color) of title compound **5**. H atoms are omitted for clarity.

There are relative differences in the corresponding bond distances, bond angles, and torsional angles among the conformers **5IA**–**5IIB**. In the C1–C19 molecule (**5I**), the two dioxane rings at major component **5IA** and minor component **5IB** are both in the half-chair conformations. The atom C18A shows maximum deviation from the dioxane ring of C14–C15–O6–C19A–C18A–O5 (r.m.s. deviation = 0.212 Å) by 0.351 Å in the major component **5IA**. The atom C19B shows maximum deviation from the ring of C14–C15–O6–C19B–C18B–O5 (rmsd = 0.201 Å) by 0.338 Å in the minor component **5IB**. The dihedral angle formed between plane of the dimethoxy-substituted benzene ring (C2–C7; rmsd = 0.004 Å) and a plane of dioxane-attached benzene ring (C12–C17; rmsd = 0.003 Å) is 47.45(4)◦ . The methoxy groups are slightly twisted from the benzene ring by torsion angle of C3–C4–O3–C10 = 10.6(2)◦ at C4 and C6–C5–O4–C11 = −5.5(2)<sup>o</sup> at C5, respectively, in the molecule **5I** (Figure 2). There are relative differences in the corresponding bond distances, bond angles, and torsional angles among the conformers **5IA**–**5IIB**. In the C1–C19 molecule (**5I**), the two dioxane rings at major component **5IA** and minor component **5IB** are both in the half-chair conformations. The atom C18A shows maximum deviation from the dioxane ring of C14–C15–O6–C19A–C18A–O5 (r.m.s. deviation = 0.212 Å ) by 0.351 Å in the major component **5IA**. The atom C19B shows maximum deviation from the ring of C14–C15–O6–C19B–C18B–O5 (rmsd = 0.201 Å ) by 0.338 Å in the minor component **5IB**. The dihedral angle formed between plane of the dimethoxy-substituted benzene ring (C2–C7; rmsd = 0.004 Å ) and a plane of dioxane-attached benzene ring (C12–C17; rmsd = 0.003Å ) is 47.45(4)<sup>o</sup> . The methoxy groups are slightly twisted from the benzene ring by torsion angle of C3–C4–O3–C10 = 10.6(2)<sup>o</sup> at C4 and C6–C5–O4–C11 = −5.5(2)<sup>o</sup> at C5, respectively, in the molecule **5I** (Figure 2).

**Figure 2.** View of the molecular structure of the independent molecule **5I** with the atom label including all hydrogens. It shows a disordered structure in the 1, 4-dioxane rings. Displacement ellipsoids are drawn at the 30% probability level. **Figure 2.** View of the molecular structure of the independent molecule **5I** with the atom label including all hydrogens. It shows a disordered structure in the 1, 4-dioxane rings. Displacement ellipsoids are drawn at the 30% probability level.

Both the dioxane ring (C33–C34–O11–C38A–C37A–O12 (rmsd 0.204 Å )) of the major component and the dioxane ring (C33–C34–O11–C38B–C37B–O12 (rmsd 0.226 Å )) of a minor component lie in the half-chair conformations in molecule **5II** as well. The maximum deviations from each dioxane ring are 0.332 Å at C37A, and 0.383 Å at C38B, respectively. For the independent molecule **5II** (C20– C38), the dihedral angle formed between the corresponding two benzene rings of (C21–C26; rmsd = Both the dioxane ring (C33–C34–O11–C38A–C37A–O12 (rmsd 0.204 Å)) of the major component and the dioxane ring (C33–C34–O11–C38B–C37B–O12 (rmsd 0.226 Å)) of a minor component lie in the half-chair conformations in molecule **5II** as well. The maximum deviations from each dioxane ring are 0.332 Å at C37A, and 0.383 Å at C38B, respectively. For the independent molecule **5II** (C20–C38), the dihedral angle formed between the corresponding two benzene rings of (C21–C26; rmsd = 0.004 Å)

, which is slightly less twisted compared to

molecule **5I**. In addition, the methoxy groups are almost coplanar with the benzene ring by the torsion

0.004 Å ) and (C31–C36; rmsd = 0.003Å ) is 34.82(2)<sup>o</sup>

(Figure 3).

dimers with R<sup>2</sup>

and (C31–C36; rmsd = 0.003Å) is 34.82(2)◦ , which is slightly less twisted compared to molecule **5I**. In addition, the methoxy groups are almost coplanar with the benzene ring by the torsion angle of C25–C24–O10–C30 = −1.5(3)◦ at C23 and C22–C23–O9–C29 = 2.6(2)<sup>o</sup> *Crystals* **2020** at C24, respectively (Figure 3). , *10*, x FOR PEER REVIEW 7 of 15

**Figure 3.** View of the molecular structure of independent molecule **5II** with the atom label including all hydrogens. It shows disordered structure in 1, 4-dioxane rings. Displacement ellipsoids are drawn at the 30% probability level. **Figure 3.** View of the molecular structure of independent molecule **5II** with the atom label including all hydrogens. It shows disordered structure in 1, 4-dioxane rings. Displacement ellipsoids are drawn at the 30% probability level.

There are distinctive discrepancies in the bond lengths and bond angles in the distorted regions of molecules **5IA**, **5IB**, **5IIA** and **5IIB**. Comparing the bond lengths between two conformers (**A** and **B**) of each independent molecule (**5I**, **5II**), the molecule **5I** revealed significant difference in bond lengths around the disordered area. For the major conformer **5IA**, the bond lengths were O(5)–C(18A) = 1.412(4) Å , C(18A)–C(19A) = 1.506(8) Å , C(19A)–O(6) =1.495(4) Å , respectively, and for the minor conformers **5IB**, those are O(5)–C(18B) = 1.513(7) Å , C(18B)–C(19B) = 1.458(13) Å , C(19B)–O(6) =1.402(6) Å , respectively. When they are compared in an inter-molecular manner, the bond lengths of O(5)–C(18B) and C(18B)–C(19B) in crystal **5I** are longer than those of the corresponding O(11)– C(37B) and C(37B)–C(38B) in crystal **5II**. Bond angles C(38B)–C(37B)–O(11) = 110.9(15)<sup>o</sup> and C(37B)– C(38B)–O(12) = 105.2(16)<sup>o</sup> in molecule **5IIB** are smaller than the corresponding bond angles O(5)– C(18B)–C(19B) = 113.2(7)<sup>o</sup> and O(6)–C(19B)–C(18B) = 106.5(8)<sup>o</sup> in molecule **5IB** (Table 2). There are distinctive discrepancies in the bond lengths and bond angles in the distorted regions of molecules **5IA**, **5IB**, **5IIA** and **5IIB**. Comparing the bond lengths between two conformers (**A** and **B**) of each independent molecule (**5I**, **5II**), the molecule **5I** revealed significant difference in bond lengths around the disordered area. For the major conformer **5IA**, the bond lengths were O(5)–C(18A) = 1.412(4) Å, C(18A)–C(19A) = 1.506(8) Å, C(19A)–O(6) =1.495(4) Å, respectively, and for the minor conformers **5IB**, those are O(5)–C(18B) = 1.513(7) Å, C(18B)–C(19B) = 1.458(13) Å, C(19B)–O(6) =1.402(6) Å, respectively. When they are compared in an inter-molecular manner, the bond lengths of O(5)–C(18B) and C(18B)–C(19B) in crystal **5I** are longer than those of the corresponding O(11)–C(37B) and C(37B)–C(38B) in crystal **5II**. Bond angles C(38B)–C(37B)–O(11) = 110.9(15)◦ and C(37B)–C(38B)–O(12) = 105.2(16)◦ in molecule **5IIB** are smaller than the corresponding bond angles O(5)–C(18B)–C(19B) = 113.2(7)◦ and O(6)–C(19B)–C(18B) = 106.5(8)◦ in molecule **5IB** (Table 2).

**Table 2.** Selected bond lengths (Å ) and bond angles ( o ) in the distorted regions of crystal **5IA**, **5IB**, **5IIA** and **5IIB**, which show distinctive discrepancy. Torsional angles ( o ) were shown for the difference **Table 2.** Selected bond lengths (Å) and bond angles (◦ ) in the distorted regions of crystal **5IA**, **5IB**, **5IIA** and **5IIB**, which show distinctive discrepancy. Torsional angles (◦ ) were shown for the difference in the methoxy group substitutions.


C(6)–C(5)–O(4)–C(11) −5.5(2) C(25)–C(24)–O(10)–C(30) −1.5(3) In the crystal, the pairs of the intermolecular C37–H37B···O11 hydrogen bonds form inversion

<sup>2</sup>(6) graph-set motifs. The dimers are linked into chains along the a axis direction by

In the crystal, the pairs of the intermolecular C37–H37B···O11 hydrogen bonds form inversion dimers with R<sup>2</sup> <sup>2</sup>(6) graph-set motifs. The dimers are linked into chains along the a axis direction by pairs of the C38–H38B···O9 hydrogen bonds in the molecule **II** (Figure 4, Table 3). *Crystals* **2020**, *10*, x FOR PEER REVIEW 8 of 15

**Figure 4.** Pairs of hydrogen bonds form an inversion dimer (orange dashed line) which are linked into chains along the *a*-axis. **Figure 4.** Pairs of hydrogen bonds form an inversion dimer (orange dashed line) which are linked into chains along the *a*-axis.

**Table 3.** Intermolecular hydrogen bonds involved in the crystal packing of compound **5** (Å and ◦ ).


Symmetry transformations used to generate equivalent atoms: #1 x+1, y, z; #2 x−1, -y+3/2, z−1/2; #3 x, −y+3/2, z+1/2; #4 −x, −y+1, −z. **Figure 4.** Pairs of hydrogen bonds form an inversion dimer (orange dashed line) which are linked into

The two molecules **5I** and **5II** are connected to each other by intermolecular hydrogen bonds C11–H11B···O12 and C29–H29B···O1 to form an ac-plane from two-dimensional supramolecules (Figure 5, Table 3). The two molecules **5I** and **5II** are connected to each other by intermolecular hydrogen bonds C11–H11B···O12 and C29–H29B···O1 to form an ac-plane from two-dimensional supramolecules (Figure 5, Table 3).

C(10)–H(10B)…O(7)#3 0.97 2.48 3.424(2) 165.6 C(37A)–H(37B)…O(11)#4 0.98 2.59 3.071(4) 110.7 Symmetry transformations used to generate equivalent atoms: #1 x+1, y, z; #2 x−1, -y+3/2, z−1/2; #3 x, **Figure 5.** A view along the b axis of the crystal packing of compound **5**. The molecule **I** and **II** are linked via intermolecular hydrogen bonds C11–H11B···O12 and C29–H29B···O1. For clarity, the hydrogen atoms not involved in H bonds are omitted. **Figure 5.** A view along the b axis of the crystal packing of compound **5**. The molecule **I** and **II** are linked via intermolecular hydrogen bonds C11–H11B···O12 and C29–H29B···O1. For clarity, the hydrogen atoms not involved in H bonds are omitted.

−y+3/2, z+1/2; #4 −x, −y+1, −z.

−y+3/2, z+1/2; #4 −x, −y+1, −z.

chains along the *a*-axis.

C(10)–H(10B)…O(7)#3 0.97 2.48 3.424(2) 165.6 C(37A)–H(37B)…O(11)#4 0.98 2.59 3.071(4) 110.7 Symmetry transformations used to generate equivalent atoms: #1 x+1, y, z; #2 x−1, -y+3/2, z−1/2; #3 x,

**Table 3.** Intermolecular hydrogen bonds involved in the crystal packing of compound **5** (Å and °).

#### *3.3. Hirshfeld Surface analysis of Compound 5 3.3. Hirshfeld Surface analysis of Compound 5*

In order to quantify the intermolecular interactions in the crystals of the titled compound **5**, a Hirshfeld surface (HS) analysis was carried out. Based on the Hirshfeld analysis on all conformers, two independent molecules (**5I** and **5II**) showed different dnorm, shape index (SI) and curvedness, however, each set of conformers **A** and **B** revealed the same Hirshfeld analysis results [46]. The 3D Hirshfeld surfaces of two independent molecules (**5I** and **5II**) were illustrated in Figure 6A,B, which maps dnorm, shape index and curvedness. The deep red spots on the dnorm Hirshfeld surfaces of each molecule represent the close contact interactions, which are mainly responsible for the significant intermolecular C–H···O interactions. Shape index and curvedness can also be used to identify the characteristic packing modes. The shape indexes of **5I** and **5II** show red concave regions on the surface around the acceptor atoms and blue regions around the donor H atoms. The maps of curvedness for **5I** and **5II** show no flat surface patches representing that there are no stacking interactions between the molecules [47]. In order to quantify the intermolecular interactions in the crystals of the titled compound **5**, a Hirshfeld surface (HS) analysis was carried out. Based on the Hirshfeld analysis on all conformers, two independent molecules (**5I** and **5II**) showed different dnorm, shape index (SI) and curvedness, however, each set of conformers **A** and **B** revealed the same Hirshfeld analysis results [46]. The 3D Hirshfeld surfaces of two independent molecules (**5I** and **5II**) were illustrated in Figure 6A,B, which maps dnorm, shape index and curvedness. The deep red spots on the dnorm Hirshfeld surfaces of each molecule represent the close contact interactions, which are mainly responsible for the significant intermolecular C–H···O interactions. Shape index and curvedness can also be used to identify the characteristic packing modes. The shape indexes of **5I** and **5II** show red concave regions on the surface around the acceptor atoms and blue regions around the donor H atoms. The maps of curvedness for **5I** and **5II** show no flat surface patches representing that there are no stacking interactions between the molecules [47].

*Crystals* **2020**, *10*, x FOR PEER REVIEW 9 of 15

**Figure 6.** (**A**) Hirshfeld surfaces of molecule **5I** mapped with dnorm, shape index and curvedness. (**B**) Hirshfeld surfaces of molecule **5II** mapped with dnorm, shape index and curvedness. **Figure 6.** (**A**) Hirshfeld surfaces of molecule **5I** mapped with dnorm, shape index and curvedness. (**B**) Hirshfeld surfaces of molecule **5II** mapped with dnorm, shape index and curvedness.

According to two-dimensional fingerprint plots analysis, the dominant interaction in each molecule **5I** and **5II** originates from H···H contacts, which are the major contributors of 43.5% and 42.5% to the total Hirshfeld surface, respectively. The contribution from the O···H/H···O contacts of 25.1% and 29.1% of each molecule **5I** and **5II** is represented by a pair of sharp spikes that are characteristic of hydrogen-bonding interactions. Other meaningful interactions include C···H/H···C According to two-dimensional fingerprint plots analysis, the dominant interaction in each molecule **5I** and **5II** originates from H···H contacts, which are the major contributors of 43.5% and 42.5% to the total Hirshfeld surface, respectively. The contribution from the O···H/H···O contacts of 25.1% and 29.1% of each molecule **5I** and **5II** is represented by a pair of sharp spikes that are characteristic of hydrogen-bonding interactions. Other meaningful interactions include C···H/H···C with contributions of 17.8% and 16.7% from **5I** and **5II**, respectively (Figure 7A–H).

with contributions of 17.8% and 16.7% from **5I** and **5II**, respectively (Figure 7A–H). The overall contribution to the total Hirshfeld surface is illustrated in Figure 8.
