Sequential Nucleophilic Aromatic Substitution Reactions of Activated Halogens

Abstract

Building blocks have been identified that can be functionalised by sequential nucleophilic aromatic substitution. Some examples are reported that involve the formation of cyclic benzodioxin and phenoxathiine derivatives from 4,5-difluoro-1,2-dinitrobenzene, racemic quinoxaline thioethers, and sulfones from 2,3-dichloroquinoxaline and (2-aminophenylethane)-2,5-dithiophenyl-4-nitrobenzene from 1-(2-aminophenylethane)-2-fluoro-4,5-dinitrobenzene. Four X-ray single-crystal structure determinations are reported, two of which show short intermolecular N–O^…N “π hole” contacts.

1. Introduction

Halogens activated to nucleophilic aromatic substitution are scaffold building blocks for functional materials and heterocycles with interesting properties (Figure 1). Some examples are listed here: 2,4-difluoronitrobenzene, 1, reacts with one or two different amines which can give porous organic materials with a flexible framework; [1,2,3] and references cited herein. 4,5-Difluoro-1,2-dinitrobenzene, 2, reacts with 1,2-disubstituted amines, alcohols, and thiols, forming N-heteroacenes, phenoxazines, and phenothiazines; [4] and references cited herein. 2,3-Dichloroquinoxaline reacts with different nucleophiles to give novel pharmaceutical building blocks [5,6]. 2,3-Dichlorothiadiazole, 4, is representative of a general field of research known as sulphur–nitrogen (S–N) chemistry pioneered by Charles W Rees [7,8,9,10]. 1,3-Difluoro-4,6-dinitrobenzene, 5, a building block for Marfey’s reagent, is useful in peptide chemistry [11,12]. 1,2-Dichloro-4,5-dicyanobenzene, 6, is a building block for substituted phthalocyanines [13].

Figure 2 shows some products that can be made from compounds 5 or 6, respectively. Compound 7 is an easily made cyclophane [14], and macrocycle 8 is a precursor to an energetic substance [15]. Phthalonitrile 9 is a phthalocyanine precursor for optical limiting in polished polycarbonate discs [16].

2. Results and Discussion

New studies are being reported with building block 2 and catechol, 10, dithiocatechol, 11, and 2-hydroxythiophenol, 12, to make dioxin 13, dithiin 14, and phenoxathiin 15, respectively (Figure 3). In the supplementary section charts for proton and carbon NMR data for all new compounds are reported.

The two nitro groups activate both halogens to sequential nucleophilic displacement by phenoxide and thiolate anions. The yields are good for these syntheses. The synthesis of compound 14 was reported by us previously, but it is included here for comparison with other data. Figure 4 shows the synthesis of racemic S-oxide, 16. Although the yield was good, the yield for the synthesis of the precursor heterocycle 15 was poor, which restricted the amount of material made. Further detailed studies were only carried out on compound 14.

Compound 15 was oxidised with meta-chloroperbenzoic (mcpba) acid in DCM at room temperature to S-oxide 16 on a small scale. Owing to the racemic nature of this S-oxide, it was difficult to obtain good crystals, possibly due to the disorder of the S-oxide grouping. The oxidation of cyclic sulphide 15 to sulfoxide 16 stopped at the sulfoxide without over-oxidation to a sulfone.

X-ray single-crystal structure determinations were carried out on compounds 13–15.

Compound 13 crystallises in the triclinic space group P$\overline{1}$ with one molecule in the asymmetric unit (Figure 5). The C1–C6 and C7–C12 rings are slightly puckered by 5.54 (6)°, which correlates with the fact that the dioxin ring is a very shallow boat with atoms CO1 and O2 displaced from the best plane of C4/C5/C7/C8 by –0.0722 (15) and –0.0917 (14) Å, respectively. The C5–O1–C8 and C4–O2–C7 bond angles are 115.48 (8) and 115.55 (8)°, respectively. Both nitro groups are twisted from their attached C1–C6 ring, by 54.43 (9)° for N1/O3/O4 and 27.21 (7)° for N2/O5/O6. In the extended structure of compound 13, the molecules are linked by weak C–H^…O interactions, but there are no identified short contacts involving the nitro groups. In unsubstituted dibenzo-p-dioxin [17] C₁₂H₈O₂, all the atoms lie on a crystallographic mirror plane, and the C–O–C bond angle is 116.4°.

Compound 14 displays monoclinic crystal symmetry (space group P2₁/n) with one molecule in the asymmetric unit (Figure 6). The outer C1–C6 and C7–C12 rings are substantially puckered by 50.89 (3)°, and the dithiin ring is well described as a boat with atoms S1 and S2 displaced from the best plane of C4/C5/C7/C8 (r.m.s. deviation = 0.001 Å) by 0.6979 (13) and 0.6723 (12) Å, respectively. The C5–S1–C7 and C4–S2–C8 bond angles are 99.84 (4) and 100.31 (5)°, respectively (mean = 100.1°); these angles are much smaller than the corresponding bond angles (via O atoms) in compound 13, which is consistent with the trend that bond angles decrease for more polarisable atoms in the same group of the periodic table [18]. In the structure [19] of unsubstituted thianthrene, C₁₂H₈S₂, the dihedral angle between the aromatic rings is 50.5°, and the mean C–S–C bond angle is 100.2°. Both nitro groups in compound 14 are twisted from their attached C1–C6 ring, by 53.72 (8)° for N1/O1/O2 and 27.41 (8)° for N2/O3/O4; these dihedral angles are notably similar to the corresponding values for 13.

In the extended structure of compound 14, the molecules are linked by weak C–H^…O and C–H^…S interactions as well as unusual short N–O^…N “π hole” contacts [20] between symmetry-related N1-nitro groups (Figure 7) with O1^…N1ⁱ = 2.8969 (13) Å and N1–O1^…N1ⁱ = 145.90 (7)° (i = ½–x, y–½, ½–z), which generate [010] chains with adjacent molecules related by the 2₁ screw axis (the van der Waals separation of O and N is about 3.07 Å). The dihedral angle between the N1 and N1ⁱ nitro groups is 69.70 (7)°.

Compound 15 crystallises with two molecules (A containing C1 and B containing C13) in the asymmetric unit (Figure 8) of space group P$\overline{1}$, both of which display disorder: in molecule A, ‘flip’ (~180° rotational) disorder about the long axis of the molecule of the O and S atoms of the oxathiine ring [occupancy of S1/O2 = 0.493 (5); occupancy of S2/O1 = 0.507 (5)] occurs as well as positional disorder of the C7–C12 ring. The B molecule also shows flip disorder [occupancy of S3/O8 = 0.180 (4); occupancy of S4/O7 = 0.820 (4)] as well as disorder of the oxygen atoms of the N3 and N4 nitro groups in 0.715 (4):0.285 (4) and 0.720 (6): 0.280 (6) ratios, respectively. The extensive disorder complicates the detailed interpretation of the ring conformations, but it may be stated that the molecules are close to planar, with dihedral angles between the C1–C6 and C7–C12 (major component) rings of 12.29 (12)° and C13–C18 and C19–C24 of 4.20 (8)°. In the extended structure of compound 15, the molecules are linked by weak C–H^…O bonds, but there are no short contacts involving the nitro groups.

The building blocks in Figure 1 are all commercially available, so more were investigated. Each chlorine atom of compound 3 is activated by a pyridine-type nitrogen atom. Compound 3 was reacted with a cheap optically pure (S) amine by a nucleophilic aromatic substitution reaction to give product 17 (Figure 9). This was reacted with a thiolate anion which is a strong nucleophile owing to its size and polarisability. Product 18 was treated with mcpba with a view to make the mono S-oxide (not drawn). Instead, the product was identified, with a clean mass spectrum, as sulfone 19 shown in Figure 9. Here, and in our previous studies, the oxidation of a cyclic sulphide stopped at the mono S-oxide, but here the acyclic sulphide smoothly converted to the sulfone. The oxidation of a cyclic sulfoxide is presumed to have a higher energy barrier. Previously, we discussed the enantiomeric fractionation of chiral sulfoxides from a silica column, which has been reported, but not for single enantiomers. The sulfoxide and sulfone have similar R_f values, which might complicate the fractionation. No X-ray single-crystal structures were obtained on compounds 17–19. The asymmetry possibly inhibits the growth of good crystals.

Either one [10] or two chlorine atoms can be displaced from 2,3-dichloroquinoxaline, 3, with butylamine (Figure 10). Since the second Cl atom is harder to displace, and ideally requires a thiolate anion as a nucleophile, the reaction was carried out in a Parr PTFE-lined pressure vessel at a higher temperature of 150 °C. The product forms in low yield but was more polar and harder to purify. In our studies on potential porous organic materials, we found that polar compounds were harder to purify, so the polarity was reduced with butylamine substituents [1,2]. For example, if butylamine was replaced with methyl, ethyl, or propylamine, no products were isolated with smaller compounds.

All four substituents on compound 2 are activated because each nitro group activates the other one as well as a para-fluorine atom (Figure 3) [21,22]. An X-ray single-crystal structure determination was carried out on compound 24.

Compound 24 crystallises in space group Pca2₁ with one molecule in the asymmetric unit (Figure 11). The morpholine ring adopts a normal chair conformation [displacements of N1 and O1 from C7 to C10 = –0.652 (4) and 0.653 (4) Å, respectively] with the exocyclic N1–C5 bond in an equatorial conformation, although the bond angle sum at N1 of 354° is suggestive of a tendency towards sp² hybridisation. The dihedral angle between the rings (all atoms) is 24.33 (11)°. The N3/O4/O5 nitro group lies close to the plane of the C1–C6 ring [dihedral angle = 9.2 (4)°], whereas N2/O2/O3 is substantially twisted [82.57 (14)°]. This can be explained by conjugation of the N3 nitro group with atom N1 via the aromatic ring (i.e., a quinoid C=N⁺ resonance form); the C2–N3 bond length [1.441 (4) Å] is clearly shorter than C1–N2 [1.474 (4) Å], and the mean of C1–C6 and C3–C4 [1.368 Å] is shorter than the mean of C1–C2, C2–C3, C4–C5, and C5–C6 [1.401 Å].

The extended structure of 24 features weak C–H^…O and C–H^…F interactions as well as notably short N2–O2^…N3ⁱⁱ (ii = x, 1+y, z) contacts (Figure 12), which lead to [010] chains with adjacent molecules related by translation: the O^…N separation is 2.839 (3) Å, the N–O^…N angle is 132.20 (19)°, and the dihedral angle between the N2 and N3ⁱⁱ nitro groups is 81.5 (3)°.

Although these reactions are feasible because one fluorine atom is easily displaced (Figure 13), the next reaction posed considerable difficulty (Figure 14).

A TLC plate run after the reaction work-up showed three spots running close together. The middle spot was eventually isolated as the pure product after running a multiple number of long (12″ × 1″) columns. The data fits for structure 26 are shown. The fluorine atom must be the first group to be displaced; otherwise, two thioethers could not be formed. The nitro group conjugated to the amine is deactivated by this conjugation. After the fluorine atom, the more reactive nitro group is displaced next. This reaction is interesting and represents a formal addition–substitution of diphenyldisulfide across the 1 and 4 positions of a benzene ring, which we believe to be a new reaction. The yield is only about 10%, but the product is pure with good data.

3. Material and Methods

IR spectra were recorded on a diamond-attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectrometer, Nicolet Summit Everest, (Thermo Fischer Scientific, 1 Ashley Road, Altrincham, Cheshire, England); Ultraviolet (UV) spectra were recorded using a Perkin Elmer Lambda 25 UV–Vis spectrometer with EtOH as the solvent (LAS Chalfont, Seer Green, Beaconsfield, England); The term sh means shoulder. ¹H and ¹³C nuclear magnetic resonance (NMR) spectra were recorded at 400 and 100.5 MHz, respectively, using a Bruker 400 spectrometer (Bruker UK Ltd., Welland House, Westwood Business Park, Coventry, England); Chemical shifts, δ, are given in ppm and measured by comparison with the residual solvent. Coupling constants, J, are given in Hz. High-resolution mass spectra were obtained at the University of Wales, Swansea, using an Atmospheric Solids Analysis Probe (ASAP) (positive mode) instrument: Xevo G2-S ASAP (Waters Ltd., Stamford Avenue, Altrincham Road, Wilmslow, England); Melting points were determined on a Cole-Palmer MP-200D Stuart digital melting point microscope (CamLab, Norman Way Ind. Estate, Over, Cambridge, England).

• 2,3-Dinitrodibenzo-[1,4]-dioxin 13

4,5-Difluoro-1,2-dinitrobenzene 2 (300 mg, 1.47 mmol) in EtOH (30 mL) was mixed with catechol (162 mg, 1.47 mmol) and Na₂CO₃ (2.0 g) and then stirred at 75 °C for 20 h. The mixture was added to water (200 mL) and allowed to stand for 1 h. This was filtered and air-dried for 2 days to give a bright yellow precipitate of the title compound (365 mg, 91%) as yellow crystals, 205–206 mp °C (from dichloromethane/light petroleum ether). λ_max (EtOH)/nm 279 (log ε 3.6) and 369 sh (3.0); ν_max (diamond) (cm^–1) 3062 w, 1626 w, 1594 w, 1537 s, 1505 s, 1486 s, 1340 s, 1305 s, 1290 s, 1199 s, 890 s, 873 s, 821 s, 765 s, 750 s, and 450 w; δ_H (400 MHz; CDCl₃), 7.05–7.10 (4H, m) and 7.89 (2H, s); δ_C (100.1 MHz; CDCl₃) 114.0, 117, 126.3, 138.5, 140.2, and 145.4; m/z (Orbitrap ASAP) 275.0300 (M⁺ + H, 100%) C₁₂H₆N₂O₆H requires 275.0304.

• 2,3-Dinitrophenoxathiine 15

4,5-Difluoro-1,2-dinitrobenzene 2 (300 mg, 1.47 mmol) in EtOH (30 mL) was mixed with 2-hydroxythiophenol (185 mg, 1.47 mmol) and Na₂CO₃ (2.0 g) and then stirred at 75 °C for 20 h. After cooling, the mixture was added to water (200 mL), extracted with DCM (100 mL) twice, followed by drying of the combined extracts over MgSO₄. The product was purified by chromatography on silica (twice). Elution with dichloromethane/light petroleum ether (40:60) gave the title compound (145 mg, 34%) as pure red crystals, 144–145 mp °C (from dichloromethane/light petroleum ether). Alternatively, after dilution of the reaction with water (200 mL) and treatment with 5 M HCl (20 mL), the product was filtered to give the title compound (140 mg, 33%). λ_max (EtOH)/nm 233 (log ε 3.6), 284 (3.6) and 400 sh (3.0); ν_max (diamond) (cm^–1) 3100 w, 1528 s, 1468 s, 1443 s, 1383 w, 1337 s, 1291 s, 1273 s, 1237 s, 893 s, 841 s, 749 s, 718 s, 682 w, and 447 w; δ_H (400 MHz; CDCl₃) 7.10 (1H, d, J = 8.0), 7.18 (1H, t, J = 8.0), 7.27–7.33 (2H, m), 7.87 (1H, s) and 8.27 (1H, s); δ_C (100.1 MHz; CDCl₃) 114.8, 116.1, 118.4, 124.6, 127.0, 127.5, 127.6, 129.9, 138.5, 142.0, 149.4, and 154.2; m/z (Orbitrap ASAP) 291.0077 (M⁺ + H, 100%) C₁₂H₆N₂O₅SH requires 291.0076.

• 2,3-Dinitrophenoxathiin-S-oxide 16

2,3-Dinitrophenoxathiin 15 (47 mg, 0.16 mmol) in DCM (30 mL) was treated with meta-chloroperbenzoic acid (mcpba) (47 mg, 0.32 mmol) for 24 h at rt. The DCM layer was diluted with more DCM (70 mL), extracted with dilute KOH) (4 pellets of KOH dissolved in 200 mL of H₂O), dried over MgSO₄, and then concentrated and purified by chromatography on silica. DCM eluted the title compound (40 mg, 81%) as a white powder, mp 191–192 °C (from dichloromethane/light petroleum ether). λ_max (EtOH)/nm 221 (log ε 4.2) and 299 (3.8); ν_max (diamond) (cm^–1) 1013 w, 1591 w, 1533 s, 1463 s, 1443 s, 1395 s, 1275 s, 1232 s, 1051 s, 840 s, 762 s, and 540 s; δ_H (400 MHz; CDCl₃) 7.59 (1H, t, J = 8.0), 7.65 (1H, J = 8.0), 7.84 (1H, J = 8.0) and 8.14 (1H, J = 8.0), 8.50 (1H, s), and 9.18 (1H, s); δ_C (100.1 MHz; CDCl₃) 117.1, 119.2, 123.6, 127.2, 128.0, 130.4, 131.6, 135.5, 136.9, 145.8, 147.9, and 152.5; m/z (Orbitrap ASAP) 307.0021 (M⁺ + H, 100%) C₁₂H₆N₂O₆S₂H requires 307.0025.

• 2-Aminophenylethane-3-chloroquinoxaline 17

2,3-Dichloroquinoxaline 3 (300 mg, 1.51 mmol), (S)-phenylethylamine (364 mg, 3.0 mmol), and Et₃N (152 mg, 1.5 mmol) in EtOH (30 mL) were heated under reflux for 48 h. After cooling, the mixture was diluted with water (200 mL) and left to stand for 1 h. The white precipitate was filtered off through a sinter and the product was collected as one fibrous mat. This was purified by chromatography on flash silica. DCM eluted the title compound (67 mg, 16%) as a clear oil (from dichloromethane/light petroleum ether). λ_max (EtOH)/nm 237 (log ε 4.0) and 358 (3.8); ν_max (diamond) (cm^–1) 3428 w, 1571 s, 1555 s, 1508 s, 1490 s, 1451 s, 1405 s, 1268 s, 1242 s, 1215 s, 1125 w, 1054 vs, 1015 w, 937 w, 829 w, 754 vs, 695 vs and 595 s; δ_H (400 MHz; CDCl₃) 1.70 (3H, d, J = 14.0), 5.48 (1H, q, J = 8.0), 5.83 (1H, d, J = 8.0), 7.30 (1H, dd, J = 8.0 and 8.0), 7.37–7.42 (3H, m), 7.49 (2H, d, J = 8.0), 7.59 (1H, t, J = 8.0), 7.72 (1H, d, J = 8.0) and 7.80 (1H, d, J = 8.0); δ_C (100.1 MHz; CDCl₃) 22.1, 50.5, 125.1, 126.2, 126.4, 127.4, 127.9, 128.7, 130.0, 136.5, 137.7, 141.3, 143.5 and 147.1; m/z (Orbitrap ASAP) 284.0955 (M⁺ + H, 100%) C₁₆H₁₄N₃ClH requires 284.0955.

• 2-Aminophenylethane-3-thiophenylquinoxaline 18

2-Aminophenylethane-3-chloroquinoxaline 17 (40 mg, 0.14 mmol) and thiophenol (64 mg, 0.58 mmol) in EtOH (30 mL) with Na₂CO₃ (0.5 g) was heated under reflux with stirring for 18 h. Upon cooling, it was diluted in water (200 mL), extracted with DCM (100 mL), dried over MgSO₄, and filtered. The product was purified by chromatography on flash silica. The column was made up with light petroleum ether 40–60. DCM eluted front by-products and then the title compound (34 mg, 67%) as a colourless oil (from dichloromethane/light petroleum ether). λ_max (EtOH)/nm 226 (log ε 3.9) and 362 (3.7); ν_max (diamond) (cm^–1) 3407 w, 1542 s, 1505 s, 1439 s, 1405 w, 1266 w, 1240 w, 1214 w, 1124 w, 1054 s, 1022 w, 756 s, 742 s, 696 s, 686 s, 608 w, 596 s and 537 w; δ_H (400 MHz; CDCl₃) 1.60 (3H, d, J = 8.0), 5.47 (1H, q, J = 8.0), 5.68 (1H, d, J = 8.0), 7.25–7.29 (1H, m), 7.31–7.36 (5H, m), 7.40–7.41(3H, m), 7.50–7.54 (3H, m), 7.69 (1H, d, J = 8.0) and 7.75 (1H, d, J = 8.0); δ_C (100.1 MHz; CDCl₃) 22.3, 50.4, 124.5, 126.1, 126.3, 127.2, 128.3, 128.6, 129.5, 130.1, 132.7, 137.4, 141.1, 143.9, 144.2 and 148.8 (two peaks are overlapping; peak at 129.5 is asymmetric); m/z (Orbitrap ASAP) 358.1374 (M⁺ + H, 100%) C₂₂H₁₉N₃SH requires 358.1378.

• 2-Aminophenylethane-3-thiophenylquinoxaline sulfone 19

2-Aminophenylethane-3-thiophenylquinoxaline 18 (35 mg, 0.098 mmol) in DCM (30 mL) was treated with mcpba (34 mg, 0.197 mmol) and stirred for 18 h at rt. The DCM layer was extracted with water (100 mL) and made basic with 5 pellets of KOH. It was then extracted with water (100 mL), dried with MgSO₄, and filtered. The product was purified by chromatography on a silica column 12 inches in length and a 1-inch-wide outer diameter. DCM eluted the title compound (11 mg, 30%) as a yellow solid, mp 111–113 °C (from dichloromethane/light petroleum ether). λ_max (EtOH)/nm 254 (log ε 4.0), 305 (3.1) and 400 (3.1); ν_max (diamond) (cm^–1) 3394 w, 3378 w, 1542 s, 1523 s, 1444 s, 1360 s, 1315 s, 1301 s, 11,250 s, 1137 s, 1087 s, 1056 s, 752 s, 732 s, 714 s, 700 s, 684 s, 631 s, 620 s, 565 s, 549 s, 475 s and 429 s; δ_H (400 MHz; CDCl₃) 1.71 (3H, d, J = 8.0), 5.49 (1H, q, J = 8.0), 7.28 (1H, t, J = 8.0 and 8.0), 7.37 (3H, t, J = 8.0 and 8.0), 7.46 (2H, d, J = 8.0), 7.57 (2H, t, J = 8.0 and 8.0), 7.61–7.63 (2H, m), 7.67 (2H, t, J = 8.0 and 8.0), 7.82 (1H, d, J = 8.0), 8.10 (2H, d, J = 8.0); δ_C (100.1 MHz; CDCl₃) 22.5, 50.2, 125.4, 126.2, 126.3, 127.2, 128.7, 128.8, 129.2, 129.8, 132.9, 134.3, 135.5, 138.6, 141.5, 143.6, 143.8 and 147.5; m/z (Orbitrap ASAP) 390.1279 (M⁺ + H, 100%) C₂₂H₁₉N₃SO₂H requires 390.1276.

• 2-Butylamino-3-chloroquinoxaline 20

2,3-Dichloroquinoxaline 3 (200 mg, 1.0 mmol) in EtOH (30 mL) was treated with butylamine (147 mg, 2.0 mmol) and triethylamine (203 mg, 2.0 mmol). The mixture was heated at 75 °C for 18 h. After cooling, the mixture was diluted with water (200 mL), extracted with DCM (100 mL), back-extracted with water (100 mL), dried with MgSO₄, and evaporated to dryness. The product was purified by flash chromatography on silica. Elution with DCM gave the title compound (167 mg, 71%) as colourless crystals, mp 44–45 °C (from dichloromethane/light petroleum ether). λ_max (EtOH)/nm 347 (log ε 3.5); ν_max (diamond) (cm^–1) 3433 s, 2962 s, 2926 s, 2858 s, 1575 s, 1555 s, 1510 s, 1460 s, 1405 s, 1291 s, 1085 s, 1048 s, 829 s, 765 s, 756 s and 587 s; δ_H (400 MHz; CDCl₃) 0.90 (3H, t, J = 8.0), 1.38 (2H, s, J = 8.0), 1.61 (2H, q, J = 8.0), 3.50 (2H, q, J = 8.0), 5.44 (1H, s, br), 7.28 (1H, t, J = 8.0 and 8.0), 7.47(1H, t, J = 8.0 and 8.0), 7.62 (1H, d, J = 8.0) and 7.70 (1H, d, J = 8.0); δ_C (100.1 MHz; CDCl₃) 13.7, 20.1, 31.0, 41.1, 124.7, 125.8, 127.9, 129.9, 136.3, 138.0, 141.2 and 148.3; m/z (Orbitrap ASAP) 236.0956 (M⁺ + H, 100%) C₁₂H₁₄N₃ClH requires 236.0954.

• 2,3-bis(Butylamino)quinoxaline 21

2,3-Dichloroquinoxaline 3 (200 mg, 1.0 mmol) in EtOH (10 mL) was treated with butylamine (147 mg, 2.0 mmol) and triethylamine (203 mg, 2.0 mmol) in a 23 mL PTFE-lined Parr Pressure Vessel. The vessel was heated at 150 °C for 18 h and then cooled. The mixture was diluted with water (200 mL), extracted with DCM (100 mL), back-extracted with water (100 mL), dried with MgSO₄, and evaporated to dryness. The product was purified by flash chromatography on silica. Elution with Et₂O/DCM (10:90) gave the title compound (18 mg, 7%) as colourless crystals, mp 111–112 °C (from dichloromethane/light petroleum ether). λ_max (EtOH)/nm 350 (log ε 3.8); ν_max (diamond) (cm^–1) 3337 s, 2957 s, 2928 s, 2860 s, 1595 s, 1555 s, 1502 s, 1455 s, 1322 s, 1203 s, 1143 s, 747 vs, 604 s, 462 s; δ_H (400 MHz; CDCl₃) 0.97 (6H, t, J = 8.0), 1.47 (4H, s, J = 8.0), 1.69 (4H, q, J = 8.0), 3.58 (4H, t, J = 8.0), 4.62 (2H, s br), 7.32 (2H, dd, J = 4.0 and 4.0) and 7.67 (2H, dd, J = 4.0); δ_C (100.1 MHz; CDCl₃) 13.6, 20.3, 31.3, 41.6, 124.5, 125.5, 136.7 and 144.3; m/z (Orbitrap ASAP) 273.2078 (M⁺ + H, 100%) C₁₆H₂₄N₄H requires 273.2079.

• 1-(2-Aminophenylethane)-2-fluoro-4,5-dinitrobenzene 23

4,5-Difluoro-1,2-dinitrobenzene 2 (300 mg, 1.47 mmol) and 2-aminophenylethane (178 mg, 1.47 mmol) in EtOH (30 mL) were treated with Et₃N (149 mg, 1.47 mmol) and refluxed for 24 h. Upon cooling, the mixture was diluted with water (200 mL), extracted with DCM (100 mL), separated, and dried over MgSO₄. After filtration and evaporation, the mixture was purified by chromatography on silica. DCM eluted the title compound (360 mg, 80%) as a yellow solid, mp 143–144 °C (from dichloromethane/light petroleum ether). λ_max (EtOH)/nm 228 (log ε 3.5) and 378 (3.4); ν_max (diamond) (cm^–1) 3373 w, 1617 s, 1541 s, 1508 s, 1475 s, 1450 s, 1386 s, 1314 s, 1292 s, 1247 s, 1209 s, 1184 s, 1119 s, 1040 s, 882 s, 845 s, 820 s, 801 s, 746 s, 697 s, 657 s, 615 s, 592 s, 533 s and 452 s; δ_H (400 MHz; CDCl₃) 1.67 (3H, d, J = 8.0), 4.63 (1H, q, J = 8.0), 5.26 (1H, s), 6.63 (1H, d, J = 4.0), 7.30–7.43 (5H, m) and 7.79 (1H, d, J = 8.0); δ_C (100.1 MHz; CDCl₃) 24.3, 53.4, 106.5, 112.2 (1C, d, J = 20), 125.5, 128.2, 129.4, 141.0 (1C, d, J = 5), 141.4, 142.9 and 148.8 (1CF, d, J = 220); m/z (Orbitrap ASAP) 306.0890 (M⁺ + H, 100%) C₁₄H₁₂N₃O₄FH requires 306.0890.

• 1-Fluoro-2-morpholino-4,5-dinitrobenzene 24

4,5-Difluoro-1,2-dinitrobenzene 2 (500 mg, 2.45 mmol), morpholine (213 mg, 2.45 mmol), and Et₃N (248 mg, 2.45 mmol) in EtOH (30 mL) were refluxed for 18 h. After cooling, the reaction was diluted with water (200 mL), left standing for 5 min, and filtered, which worked well. The filtrate was yellow. The product was a single pure spot by TLC. It was air-dried to give the title compound (587 mg, 88%) as a yellow solid, mp 167–168 °C (from dichloromethane/light petroleum ether). λ_max (EtOH)/nm 380 (log ε 3.2); ν_max (diamond) (cm^–1) 1609 s, 1526 s, 1504 s, 1368 s, 1320 s, 1304 s, 1250 s, 1206 s, 1111 s, 1066 w, 1011 s, 922 s, 870 s, 841 s, 804 s, 750 s, 719 s, 658 s, 631 s, 596 s, 559 s and 424 w; δ_H (400 MHz; CDCl₃) 3.38 (4H, t, J = 5.0), 3.90 (4H, t, J = 5.0), 7.16 (1H, d, J = 4.0) and 7.77 (1H, d, J = 8.0); δ_C (151.0 MHz; CDCl₃) 49.7, 66.3, 112.9, 114.5 (1C, d, J _C-F = 24.0), 132.9, 141.6, 144.2 (1C, d, J-C = 24.0) and 153.0 (1C, d, J _C-F = 172.0) ; m/z (Orbitrap ASAP) 272.0679 (M⁺ + H, 100%) C₁₀H₁₀N₃O₅FH requires 272.0683.

• 1-Fluoro-2-butylamino-4,5-dinitrobenzene 25

4,5-Difluoro-1,2-dinitrobenzene 2 (500 mg, 2.45 mmol), butylamine (179 mg, 2.45 mmol), and Et₃N (248 mg, 2.45 mmol) in EtOH (30 mL) were refluxed for 18 h. After cooling, the reaction was diluted with water (200 mL), treated with cHCl (2 mL), left standing for 2 h, and filtered, which worked well until the end. It was air-dried to give the title compound (458 mg, 73%) as a yellow solid, mp 95–96 °C (from dichloromethane/light petroleum ether). λ_max (EtOH)/nm 382 (log ε 3.4); ν_max (diamond) (cm^–1) 3341 s, 1617 s, 1542 s, 1504 s, 1435 w, 1392 w, 1369 w, 1297 s, 1190 s, 1077 s, 882 s, 806 s, 7703 s, 655 s and 587 s; δ_H (400 MHz; CDCl₃) 1.01 (3H, d, J = 7.0), 1.47 (2H, sextet, J = 7.0), 1.69 (2H, quintet, J = 7.0), 3.3 (2H, m), 4.9 (1H, s, br NH), 6.81 (1H, d, J-C = 12.0) and 7.76 (1H, d, J-C = 12.0); δ_C (100.1 MHz; CDCl₃) 13.6, 20.1, 30.7, 42.8, 105.1 (1C, d_J-C = 4.0), 112.2 (1C, d_J-C = 23), 128.0 (1C, d_J-C = 10.0), 142.4 (1C, d_J-C = 10.0), 143.5, 148.7 (1C, d_J-C = 240.0); m/z 258.0889 (Orbitrap ASAP) (M⁺ + H, 100%) C₁₀H₁₂N₃O₄FH requires 258.0890.

• 1-(2-Aminophenylethane)-2,5-dithiophenyl-4-nitrobenzene 26

1-(2-Aminophenylethane)-2-fluoro-4,5-dinitrobenzene 23 (100 mg, 0.327 mmol), thiophenol (36 mg, 0.327 mmol), and Na₂CO₃ (500 mg) in EtOH (30 mL) were heated under reflux with stirring for 24 h. After cooling, the reaction was diluted with water (200 mL), extracted with DCM (100 mL), dried over MgSO₄, and filtered. After evaporation, the mixture was purified by chromatography on silica. DCM eluted the title compound (16 mg, 11%) as a yellow solid, mp 59–60 °C (from dichloromethane/light petroleum ether). Multiple numbers of columns were required to obtain pure product owing to close running spots thought to be diphenyldisulfide and starting material. λ_max (EtOH)/nm 240 (log ε 4.0), 297 (3.95) and 373 (3.85); ν_max (diamond) (cm^–1) 1575 s, 1544 s, 1509 s, 1473 s, 1438 s, 1294 vs, 1247 vs, 1118 s, 1073 s, 1021 s, 999 s, 967 s, 907 s, 831 s, 737 vs, 687 vs, 551 s and 429 s; δ_H (400 MHz; CDCl₃) 1.27 (3H, d, J = 8.0), 3.92 (1H, q, J = 8.0), 6.51 (2H, d, J = 8.0), 7.12 (2H, t, J = 8.0 and 8.0), 7.17–7.21 (3H, m), 7.26 (1H, d, J = 8.0), 7.29–7.30 (4H, m), 7.42–7.43 (3H, m), 7.52–7.55 (1H, m) and 8.57 (1H, s); δ_C (100.1 MHz; CDCl₃) 24.3, 52.8, 107.9, 112.0, 125.3, 126.7, 127.2, 127.6, 128.7, 129.3, 129.8, 130.1, 130.6, 134.1, 134.7, 135.6, 136.2, 142.3, 145.2 and 150.6; m/z (Orbitrap ASAP) 459.1199 (M⁺ + H, 100%) C₂₆H₂₂N₂O₂S₂H requires 459.1201; 369.1071 (M⁺ + H, 100%) C₂₀H₁₇N₂O₂SF requires 369.1062

Crystal Structure Determinations

The crystal structures of 13, 14, 15, and 24 (all recrystallised from the mixed solvents of dichloromethane/light petroleum ether) were established using intensity data collected at 100 K on a Rigaku CCD diffractometer using either Mo Kα radiation (13, 14, and 15) or Cu Kα radiation (24). The structures were routinely solved by dual-space methods using SHELXT [23], and the structural models were completed and optimised by refinement against |F|² with SHELXL-2019 [24]. Extensive disorder was found for 15. The H atoms were placed in idealised locations (C–H = 0.95–0.98 Å) and refined as riding atoms with U_iso(H) = 1.2U_eq(carrier). Full details of the structures and refinements are available in the deposited cifs.

• Crystal data for compound 13 C₁₂H₆N₂O₆, yellow plate, 0.19 × 0.09 × 0.03 mm, M_r = 274.19, triclinic, space group P$\overline{1}$ (No. 2), a = 7.8050 (2) Å, b = 8.1532 (3) Å, c = 8.9461 (2) Å, α = 97.688 (2)°, β = 99.428 (2)°, γ = 94.297 (2)°, V = 553.82 (3) ų, Z = 2, Mo Kα radiation (λ = 0.71073 Å),T = 100 K, μ = 0.136 mm^–1, ρ_calc = 1.644 g cm^–3, 26,948 reflections measured (4.7 ≤ 2θ ≤ 61.0°), 2919 unique (R_Int = 0.040), R(F) = 0.039 [2919 reflections with I > 2σ(I)], wR(F²) = 0.113 (all data), Δρ_min,max (e Å^–3) = –0.29, +0.47, CCDC deposition number 2362025.
• Crystal data for compound 14 C₁₂H₆N₂O₄S₂, yellow plate, 0.12 × 0.07 ×0.01 mm, M_r = 306.31, monoclinic, space group P2₁/n (No. 14), a = 16.4666 (3) Å, b = 4.17460 (10) Å, c = 17.5585 (4) Å, β = 93.833 (2)°, V = 1204.30 (5) ų, Z = 4, Mo Kα radiation (λ = 0.71073 Å), T = 100 K, μ = 0.457 mm^–1, ρ_calc = 1.689 g cm^–3, 52,290 reflections measured (4.7 ≤ 2θ ≤ 76.2°), 6238 unique (R_Int = 0.035), R(F) = 0.037 [4630 reflections with I > 2σ(I)], wR(F²) = 0.098 (all data), Δρ_min,max (e Å^–3) = –0.24, +0.61, CCDC deposition number 2362026.
• Crystal data for compound 15 C₁₂H₆N₂O₅S, orange rod, 0.44 × 0.15 × 0.07 mm, M_r = 290.25, triclinic, space group P$\overline{1}$ (No. 2), a = 7.89759 (13) Å, b = 11.40431 (17) Å, c = 14.0329 (2) Å, α = 70.1769 (13)°, β = 87.4953 (12)°, γ = 79.3130 (13)°, V = 1168.13 (3) ų, Z = 4, Mo Kα radiation (λ = 0.71073 Å), T = 100 K, μ = 0.300 mm^–1, ρ_calc = 1.650 g cm^–3, 113,652 reflections measured (3.1 ≤ 2θ ≤ 61.0°), 7132 unique (R_Int = 0.056), R(F) = 0.078 [6713 reflections with I > 2σ(I)], wR(F²) = 0.166 (all data), Δρ_min,max (e Å^–3) = –0.74, +0.89, CCDC deposition number 2362027.
• Crystal data for compound 24 C₁₀H₁₀FN₃O₅, yellow slab, 0.05 × 0.04 × 0.02 mm, M_r = 271.21, orthorhombic, space group Pca2₁ (No. 29), a = 18.1738 (6) Å, b = 4.60825 (14) Å, c = 13.3823 (5) Å, V = 1120.76 (7) ų, Z = 4, Cu Kα radiation (λ = 1.54184 Å), T = 100 K, μ = 1.229 mm^–1, ρ_calc = 1.607 g cm^–3, 8299 reflections measured (9.7 ≤ 2θ ≤ 140.2°), 1970 unique (R_Int = 0.038), R(F) = 0.031 [1804 reflections with I > 2σ(I)], wR(F²) = 0.078 (all data), flack absolute structure parameter 0.08 (11), Δρ_min,max (e Å^–3) = –0.17, +0.17, CCDC deposition number 2362028.

4. Conclusions

Further chemistry is developed for substrates with two halogens activated for nucleophilic displacement by strong electron withdrawing groups. The use of compound 2 gave dinitrated heterocyclic benzodioxin 13, dithiin 14, and phenoxathiine 15. All three heterocycles gave satisfactory X-ray single-crystal structure data, but phenoxathiine 15 was disordered. The cyclic thioether of compound 15 was readily oxidised with mcpba to racemic sulfoxide 16 without over-oxidation to the sulfone occurring. The chemistry of this intermediate was not developed [21] any further because of the low yield for the formation of heterocycle 15. The yield was lower than for the two symmetrical systems 13 and 14. Presumably, there is a molecular strain in the heterocycle because it is not planar but rather folded with a butterfly shape. As expected, one or two fluorine atoms are easily displaced with compound 2 [3] New aromatic derivatives 23, 24, and 25 are reported here. This leaves a further activated fluorine atom and two nitro groups, which both activate each other. A thiol was chosen to react with compound 23 because it is polarisable owing to its large size, making it a good nucleophile. The F atom was displaced, followed by the most reactive nitro group. This gave an interesting 1,4-bis(thiophenyl)benzene derivative 26, which might be a new reaction not requiring metallic catalysis such as Pd, Pd(II), or Cu(II).