Synthesis of Quinonoid Analogues of Diospyrin

Abstract

Diospyrin and its analogues have been known for their antimycobacterial properties. Significant efforts have been made towards the synthesis of structural analogues of diospyrin with improved biological activities. We report here the synthesis of four novel analogues of diospyrin via a Suzuki cross coupling between bromonaphthoquinones and aryl- or naphthylboronic acids in the presence of tetrakis(triphenylphosphine)palladium(0) as catalyst, followed by selective demethylation of the intermediates.

Mycobacterium tuberculosis (TB) infection is an acknowledged serious worldwide threat. The WHO estimates that between 2000 and 2020, nearly one billion people will be newly infected, 200 million people will become severely ill, and in the order of 35 million people will die from TB. Present treatment regimes for TB are based on a multidrug therapy in which three or four antituberculosis drugs are administered for six to nine months for sensitive cases and longer for drug resistance TB. These drugs unfortunately have serious side effects and they also do not kill latent bacilli. [¹] No new antibiotics have been developed against any mycobacteria causing health problems since the 1970s. Problems for multidrug resistance tubercle bacilli are manifesting themselves for various drug treatment regimes and, thus, there is an urgent need for novel therapeutic agents that can provide reliable and effective treatment regimes against TB. [²]

More than 2000 naturally occurring quinones, viz., anthraquinones, naphthoquinones, and benzoquinones are known to be widely distributed in nature as pigments and as intermediates in cellular respiration and photosynthesis. [³] [4] Some quinones play important roles in the biochemistry of energy production and serve as vital links in the respiratory chain of living cells. These compounds act as inhibitors of electron transport, uncouplers of oxidative phosphorylation, and give rise to a wide range of cytostatic and anti-proliferative activities. [5] They essentially provide a defense role as a result of their effectiveness in inhibiting the growth of bacteria, fungi, or parasites [6] [7] and this is the reason that a number of them display antimicrobial and anticancer activities. [8]

Diospyrin, an orange-red bisnaphthoquinone that is present in the heartwood of many species of diospyros trees, is well known for its antimycobacterial activity. [9] Sidhu and Pardhasaradhi determined its correct structure, in which a naphthoquinone linkage to the non-quino­noidal aryl ring of another naphthoquinone moiety viz., between C2 and C6′ is apparent (Figure  [¹] ). [¹0] [¹¹]

To date the only synthesis of diospyrin the authors are aware of has been reported by Yoshida and Mori. [¹²] In addition, diospyrin and its analogues have been investigated for their antimycobacterial properties. [¹³-¹5] Thus diospyrin was envisaged to be a potential lead molecule and scaffold for the synthesis of new binaphthalene systems that could eventually be transformed into bisnaphthoquinones with a view to evaluating their biological activity against different strains of Mycobacterium tuberculosis and selected cancer cell lines. In addition we also wanted to investigate whether naphthoquinone-benzoquinone systems were able to elicit similar activity and, thus, two targets were chosen for this evaluation. The results of all evaluations, which have demonstrated good promise, will be published elsewhere.

Synthesis of the first bisnaphthoquinone 7a is summarized in Schemes  [¹] -  [³] . In achieving this, it was necessary to prepare the naphthalene building blocks 2a and 5a (Schemes  [¹] and  [²] ). Thus for the synthesis of bromonaphthoquinone 2a, condensation between isoprene and 2,5-dibromo-1,4-benzoquinone, [¹6] in which the bromine atom is expected to direct the regioselectivity of the Diels-Alder­ protocol, [¹7] it was indeed found that the desired non-aromatic adduct 1 was produced in 64% isolated yield. This was followed by aromatization by using a method given by Ho et al., [¹8] an equivalent of the oxidant chloranil in boiling benzene afforded bromoquinone 2a in 75% yield (Scheme  [¹] ). For the second naphthalene moiety 5a, bromoquinone 2a was reduced using tin(II) chloride [¹9] to afford the bromonaphthalenediol 3 in which, importantly, the bromine had been retained, and this was followed by methylation with potassium carbonate and dimethyl sulfate in boiling acetone under vigorous stirring to furnish dimethyl ether 4a in 77% yield (Scheme  [¹] ). [²0]

Metal-halogen exchange of 4a with butyllithium and subsequent reaction with trimethyl borate at -78 ˚C afforded the corresponding boronic acid 5a in 70% yield (Scheme  [²] ), which was immediately used in the next stage of the synthesis. [¹²] It was observed that for optimum yields, addition of aqueous hydrochloric acid to hydrolyze the initial borate has to be very carefully controlled. Suzuki­ coupling between naphthoquinone 2a and boronic acid 5a in the presence of tetrakis(triphenylphosphine)palladium(0) as catalyst and aqueous sodium carbonate under reflux in benzene for 16 hours afforded the binaphthalene product 6a as red needles in 62% yield (Scheme  [³] ). [²¹] [²²] Unfortunately, all attempts to demethylate adduct 6a with boron tribromide and aluminum trichloride in dichloromethane at low temperature proved to be unsuccessful in our hands and, thus, final oxidative demethylation of 6a with aqueous cerium(IV) ammonium nitrate was successfully effected to afford the bisnaphthoquinone 7a in a fair yield of 70%. [²³]

In the second of our target molecules, treatment of the known 2-bromo-1,4,5-trimethoxy-7-methylnaphthalene (4b) [¹²] with butyllithium and trimethyl borate at -78 ˚C afforded the expected boronic acid 5b in a good yield of 75% (Scheme  [²] ) and this compound was immediately used in the coupling protocol described above, with 2-bromo-5-methoxy-7-methyl-1,4-naphthoquinone (2b) [¹²] to produce the binaphthalene 6b in 63% yield after chromatography. Oxidative demethylation of 6b using a similar protocol described earlier afforded the bisnaphthoquinone 7b in 65% yield (Scheme  [³] ). The symmetry of the molecule was exemplified in the rather uncomplicated ^¹H and ^¹³C NMR spectra.

The first of our naphthoquinone-benzoquinone target molecules involved coupling of naphthoquinone 2a with boronic acid 8 under the normal Suzuki protocol to afford naphthoquinone 9a in a good 76% yield. Finally, oxidative demethylation of 9a under conditions used earlier afforded the final biquinone 10a in 71% yield (Scheme  [4] ). Due to the previous difficulties we experienced in de­methylating bisnaphthoquinone 7b, in order to evaluate the influence of a peri-hydroxy group on activity [¹5] we chose another simpler example as identified in 11. Thus coupling between the two partners, namely 2-bromo-5-methoxy-7-methyl-1,4-naphthoquinone (2b) and boronic acid 8 afforded the naphthoquinone 9b in 63% yield. This was followed by oxidative demethylation to produce biquinone 10b in 72% yield. Finally demethylation of the peri-methoxy group employing aluminum trichloride in dichloromethane at 25 ˚C afforded the hydroxyquinone 11 in 55% yield. [²4]

In summary, a reasonably simple protocol has thus been established for the synthesis of naphthoquinone-naphthoquinone as well as naphthoquinone-benzoquinone molecules in which the quinonoidal moieties are directly linked.

Nuclear magnetic resonance spectra were recorded using a Varian 200 MHz spectrometer. All spectra were recorded at 20 ˚C in CDCl₃. Assignments of peaks in ^¹H and ^¹³C NMR spectra with the same superscript may be interchanged. Mass spectra were recorded on a Finnigan-Matt Ion Trap Detector spectrometer at 70 eV with automatic gain control. HRMS were recorded on a modified AEI-902 High Resolution Mass Spectrometer at the University of the Witwatersrand, Johannesburg. Infrared spectra were recorded as Nujol mulls on a Perkin Elmer 1000PC Fourier Transform spectrophotometer. Melting points are uncorrected and were recorded on a Fisher-Johns Melting Point Apparatus. Column chromatography was carried out using Merck Kieselgel 60 (70-230 mesh) as dry columns. Pre-adsorption was carried out on Merck Kieselgel 60 (35-70 mesh). PLC was performed on glass plates coated with silica gel with UV254 indicator and as a 1.0 mm thick layer, while TLC was carried out on aluminum plates coated with Merck Kieselgel 60 F₂₅₄. The residue obtained upon workup refers to material obtained from the dried (MgSO₄) organic extract after filtration and solvent removal. Hexane refers to the fraction of boiling point 68-72 ˚C. All solvents were purified by distillation and, if necessary, were dried according to standard methods.

2-Bromo-7-methyl-5,8-dihydro-1,4-naphthoquinone (1)

To a soln of 2,5-dibromo-1,4-benzoquinone [¹6] (2.68 g, 10.0 mmol) in THF (20 mL) at 24 ˚C under an N₂ atmosphere was added a soln of commercially available isoprene (0.68 g, 10.00 mmol) in THF (10 mL) dropwise over 15 min. The resulting soln was heated under reflux for 8 h and then cooled to 24 ˚C. The residue obtained upon workup was chromatographed (EtOAc-hexane, 1:19) to afford 1 (1.64 g, 64%) as bluish-black needles; mp 73-75 ˚C (EtOH).

IR (Nujol): 1660 (m, C=O), 1651 (m, C=O), 1601 (w, Ar), 1585 cm^-¹ (w, Ar).

^¹H NMR (200 MHz, CDCl₃): δ = 1.77 (s, 3 H, 7-CH₃), 3.05 (m, 4 H, H5, H8), 5.48 (m, 1 H, H6), 7.24 (s, 1 H, H3).

^¹³C NMR (50 MHz, CDCl₃): δ = 22.9 (CH₃), 25.3 (C5)^a, 29.5 (C8)^a, 116.6 (C6), 130.2 (C2)^b, 137.2 (C7)^b, 137.9 (C3), 139.4 (C4a)^c, 140.2 (C8a)^c, 179.3 (C1)^d, 184.5 (C4)^d.

HRMS: m/z [M]⁺ calcd for C₁₁H₉BrO₂: 251.9785; found: 251.9787.

Anal. Calcd for C₁₁H₉BrO₂: C, 52.2; H, 3.6. Found: C, 52.4; H, 3.8.

2-Bromo-7-methyl-1,4-naphthoquinone (2a)

A mixture of 1 (1.82 g, 7.10 mmol), chloranil (1.74 g, 7.10 mmol), and benzene (30 mL) was heated under reflux for 30 h. The residue obtained upon workup was chromatographed (EtOAc-hexane, 1:19) to afford 2a (1.35 g, 75%) as yellow needles; mp 124-126 ˚C (EtOH).

IR (Nujol): 1674 (s, C=O), 1650 (s, C=O), 1597 (m, Ar), 1587 cm^-¹ (m, Ar).

^¹H NMR (200 MHz, CDCl₃): δ = 2.51 (s, 3 H, 7-CH₃), 7.49 (s, 1 H, H3), 7.57 (dd, J = 8.0, 1.2 Hz, 1 H, H6), 7.96 (d, J = 1.2 Hz, 1 H, H8), 7.98 (d, J = 8.0 Hz, 1 H, H5).

^¹³C NMR (50 MHz, CDCl₃): δ = 21.9 (CH₃), 127.2 (C3)^a, 128.3 (C6)^a, 129.7 (C2)^b, 131.0 (C7)^b, 135.2 (C5)^c, 139.9 (C4a)^d, 140.5 (C8)^c, 145.6 (C8a)^d, 179.0 (C1)^e, 182.4 (C4)^e.

HRMS: m/z [M]⁺ calcd for C₁₁H₇BrO₂: 251.9629; found: 251.9631.

Anal. Calcd for C₁₁H₇BrO₂: C, 52.6; H, 2.8. Found: C, 52.8; H, 2.6.

2-Bromo-7-methylnaphthalene-1,4-diol (3)

To a stirred suspension of 2a (1 g, 3.98 mmol) in EtOH (40 mL) at 50 ˚C was added a soln of SnCl₂ (3.1 g, 13.90 mmol) in concd HCl (5 mL). The mixture was stirred at this temperature for 45 min, it was poured into cold H₂O (150 mL), and the solid material was filtered and washed with H₂O to afford 3 (0.74g, 74%) as white needles­; mp ˜115 ˚C (dec.) (benzene).

IR (Nujol): 3297 (m, OH), 1595 cm^-¹ (m, Ar).

^¹H NMR (200 MHz, CDCl₃): δ = 2.54 (s, 3 H, 7-CH₃), 5.56 (s, 1 H, OH), 6.81 (s, 1 H, H3), 7.36 (dd, J = 8.5, 1.6 Hz, 1 H, H6), 7.95 (d, J = 1.6 Hz, 1 H, H8), 7.97 (d, J = 8.5 Hz, 1 H, H5).

^¹H NMR (200 MHz, acetone-d ₆): δ = 2.50 (s, 3 H, 7-CH₃), 6.92 (s, 1 H, H3), 7.36 (dd, J = 8.4, 1.6 Hz, 1 H, H6), 7.77 (s, 1 H, 1-OH)^a, 7.98 (d, J = 1.6 Hz, 1 H, H8), 8.07 (d, J = 8.4 Hz, 1 H, H5), 8.83 (s, 1 H, 4-OH)^a.

^¹³C NMR (50 MHz, acetone-d ₆): δ = 12.9 (CH₃), 95.4 (C2), 101.8 (C3)^a, 113.0 (C6)^a, 114.2 (C5)^a, 115.4 (C8)^a, 118.4 (C7)^a, 119.3 (C4a)^b, 128.0 (C8a)^b, 133.8 (C1)^c, 138.9 (C4)^c.

HRMS: m/z [M]⁺ calcd for C₁₁H₉BrO₂: 251.9785; found: 251.9782.

Anal. Calcd for C₁₁H₉BrO₂: C, 52.2; H, 3.6. Found: C, 52.5; H, 3.4.

2-Bromo-1,4-dimethoxy-7-methylnaphthalene (4a)

To a soln of 3 (0.73 g, 2.89 mmol) in anhyd acetone (20 mL) was added anhyd K₂CO₃ (4.79 g, 34.68 mmol). Me₂SO₄ (1.82 g, 1.36 mL, 14.40 mmol) was then added in one portion and the mixture was heated and vigorously stirred under reflux for 20 h. It was then cooled to 25 ˚C and filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in Et₂O (50 mL) and Et₃N (1.46 g, 2.0 mL, 14.40 mmol) was added. The mixture was stirred at 25 ˚C for 20 min and the soln was washed with 1 M HCl (2 × 20 mL) and H₂O (1 × 25 mL). The residue obtained upon workup was chromatographed (EtOAc-hexane, 1:5) to afford 4a (0.62g, 77%) as colorless needles; mp 73-74 ˚C (EtOH).

IR (Nujol): 1626 (w, Ar), 1587 cm^-¹ (m, Ar).

^¹H NMR (200 MHz, CDCl₃): δ = 2.54 (s, 3 H, 7-CH₃), 3.94 (s, 3 H, OMe), 3.96 (s, 3 H, OMe), 6.81 (s, 1 H, H3), 7.33 (dd, J = 8.4, 1.6 Hz, 1 H, H6), 7.81 (d, J = 1.6 Hz, 1 H, H8), 8.09 (d, J = 8.4 Hz, 1 H, H5).

^¹³C NMR (50 MHz, CDCl₃): δ = 22.0 (CH₃), 55.9 (OMe), 61.4 (OMe), 107.3 (C3), 112.1 (C2), 121.0 (C6)^a, 122.6 (C5)^a, 124.1 (C7)^a, 128.0 (C8)^a, 129.3 (C4a)^b, 137.4 (C8a)^b, 150.6 (C1)^c, 152.4 (C4)^c.

HRMS: m/z [M]⁺ calcd for C₁₃H₁₃BrO₂: 280.0098; found: 280.0099.

Anal. Calcd for C₁₃H₁₃BrO₂: C, 55.5; H, 4.7. Found: C, 55.8; H, 4.4.

1,4-Dimethoxy-7-methylnaphthalen-2-ylboronic Acid (5a); Typical Procedure

A 1.28 M soln of BuLi (1.67 mL, 2.14 mmol, 1.2 equiv) was added dropwise to a stirred soln of 4a (500 mg, 1.78 mmol) in anhyd THF (10 mL) at -78 ˚C. The mixture was stirred at this temperature under an N₂ atmosphere for 15 min, during which time the mixture color went from colorless to lime green. B(OMe)₃ (1.0 mL, 0.92 g, 8.90 mmol, 5.0 mol equiv) was then added dropwise causing the mixture to become clear again. The mixture was stirred at -78 ˚C for a further 30 min and then allowed to warm to 24 ˚C over 20 h. The mixture was then cooled to 0 ˚C and 5% aq HCl was added until the pH was ˜6. The aqueous phase was extracted with CH₂Cl₂ (3 × 30 mL) to afford 5a (308 mg, 70%), which was immediately used in the next reaction.

^¹H NMR (200 MHz, CDCl₃): δ = 2.52 (s, 3 H, 7-CH₃), 3.55 (s, 3 H, OMe), 3.81 (s, 3 H, OMe), 5.58 [s, 2 H, B(OH)₂], 6.57 (s, 1 H, H3), 7.57 (dd, J = 8.0, 1.2 Hz, 1 H, H6), 7.97 (d, J = 1.2 Hz, 1 H, H8), 8.02 (d, J = 8.0 Hz, 1 H, H5).

1′,4′-Dimethoxy-7,7′-dimethyl-2,2′-binaphthalene-1,4-dione (6a); Typical Procedure

A mixture of 2a (314 mg, 1.25 mmol) and Pd(PPh₃)₄ (150 mg, 0.13 mmol) in benzene (20 mL) was stirred for 0.5 h at 24 ˚C under an N₂ atmosphere. Aq 2 M Na₂CO₃ (1.0 mL) and 5a (307 mg, 1.25 mmol) in benzene (20 mL) were added successively. The mixture was heated under reflux for 16 h with vigorous stirring. The cooled resulting mixture was extracted with CH₂Cl₂ and the residue obtained upon workup was chromatographed (EtOAc-hexane, 3:7) to afford 6a (290 mg, 62%) as red crystals; mp 141-143 ˚C (EtOAc-hexane).

IR (Nujol): 1664 (s, C=O), 1657 (m, C=O), 1597 cm^-¹ (m, Ar).

^¹H NMR (200 MHz, CDCl₃): δ = 2.53 (s, 3 H, 7′-CH₃), 2.55 (s, 3 H, 7-CH₃), 3.74 (s, 3 H, OMe), 3.97 (s, 3 H, OMe), 6.56 (s, 1 H, H3′), 7.17 (s, 1 H, H3), 7.38 (dd, J = 8.4, 1.4 Hz, 1 H, H6′), 7.59 (dd, J = 7.6, 1.0 Hz, 1 H, H6), 7.87 (d, J = 1.4 Hz, 1 H, H8′), 8.00 (d, J = 1.0 Hz, 1 H, H8), 8.05 (d, J = 7.6 Hz, 1 H, H5), 8.16 (d, J = 8.4 Hz, 1 H, H5′).

^¹³C NMR (50 MHz, CDCl₃): δ = 21.9 (CH₃), 22.0 (CH₃), 55.7 (OMe), 62.4 (OMe), 104.0 (C3′), 108.8 (C2′), 118.0 (C2), 121.5 (C6)^a, 122.4 (C6′)^a, 126.3 (C5′)^b, 127.4 (C8′)^b, 128.7 (C3)^b, 130.0 (C7′)^c, 130.3 (C4a′)^c,132.5 (C8a′)^c, 134.5 (C5)^d, 136.8 (C7)^d, 137.5 (C8)^d, 145.0 (C1′)^e, 147.7 (C4a)^e, 147.9 (C8a)^e, 151.7 (C4′)^e, 184.4 (C1)^f, 185.1 (C4)^f.

HRMS: m/z [M]⁺ calcd for C₂₄H₂₀O₄: 372.1361; found: 372.1299.

Anal. Calcd for C₂₄H₂₀O₄: C, 77.4; H, 5.4. Found: C, 77.6; H, 5.2.

7,7′-Dimethyl-2,2′-binaphthalene-1,1′,4,4′-tetrone (7a); Typical Procedure

A suspension of 6a (200 mg, 0.54 mmol) in a mixture of MeCN (18 mL) and H₂O (8 mL) was cooled to 0 ˚C. Over the course of 10 min a cooled soln of CAN (1.10 g, 2.00 mmol) in a mixture of MeCN (12 mL) and H₂O (12 mL) was added to the suspension. The mixture was stirred for 20 min and allowed to warm to 24 ˚C over 30 min. The mixture was diluted with H₂O (100 mL) and extracted with CH₂Cl₂. The residue obtained upon workup was chromatographed (EtOAc-hexane, 2:3) to afford 7a (138 mg, 70%) as yellow crystals; mp 179-181 ˚C (EtOH).

IR (Nujol): 1668 (s, C=O), 1657 (s, C=O), 1599 (m, Ar), 1587 cm^-¹ (m, Ar).

^¹H NMR (200 MHz, CDCl₃): δ = 2.52 (s, 3 H, 7′-CH₃)^a, 2.54 (s, 3 H, 7-CH₃)^a, 6.93(s, 1 H, H3′)^b, 7.26 (s, 1 H, H3)^b, 7.60 (dd, J = 8.2, 2.0 Hz, 2 H, H6′, H6), 7.93 (d, J = 2.0 Hz, 1 H, H8′)^c, 8.01 (d, J = 8.2 Hz, 1 H, H5′)^d, 8.03 (d, J = 2.0 Hz, 1 H, H8)^c, 8.05 (d, J = 8.2 Hz, 1 H, H5)^d.

^¹³C NMR (50 MHz, CDCl₃): δ = 21.9 (CH₃), 29.7 (CH₃), 126.7 (C3′)^a, 127.4 (C3)^a, 127.6 (C6′)^a, 128.2 (C6)^a, 129.2 (C2′)^b, 129.8 (C2)^b, 131.0 (C7′)^c, 131.7 (C7)^c, 135.0 (C5′)^d, 135.4 (C5)^d,137.8 (C4a′)^e, 138.1 (C8a′)^e, 140.0 (C4a)^e, 144.3 (C8a)^e, 145.5 (C8′)^f, 145.8 (C8)^f, 177.3 (C1′)^g, 180.0 (C4′)^g, 182.0 (C1)^g, 183.8 (C4)^g.

(HRMS: m/z [M]⁺ calcd for C₂₂H₁₄O₄: 342.0892; found: 342.0888.

Anal. Calcd for C₂₂H₁₄O₄: C, 77.2; H, 4.1. Found: C, 77.3; H, 4.3.

1,4,5-Trimethoxy-7-methylnaphthalen-2-ylboronic Acid (5b)

Following the typical procedure for 5a using 1.32 M soln of BuLi (2.90 mL, 3.88 mmol, 1.1 equiv), 4b [¹²] (1.1 g, 3.53 mmol), anhyd THF (15 mL), and B(OMe)₃ (2.0 mL, 1.83 g, 17.65 mmol, 5.0 equiv) gave 5b (0.73 g, 75%), which was immediately used without further purification.

1′,4′,5,5′-Tetramethoxy-7,7′-dimethyl-2,2′-binaphthalene-1,4-dione (6b)

Following the typical procedure for 6a using 2b [¹²] (800 mg, 2.90 mmol), Pd(PPh₃)₄ (340 mg, 0.30 mmol), and benzene (30 mL) and aq 2 M Na₂CO₃ (3.0 mL), 5b (780 mg, 2.80 mmol), and benzene (20 mL); chromatography (EtOAc-hexane, 1:1) afforded 6b (782 mg, 63%) as reddish brown needles; mp 84-86 ˚C (EtOAc-hexane).

IR (Nujol): 1668 (m, C=O), 1651 (m, C=O), 1599 cm^-¹ (m, Ar).

^¹H NMR (200 MHz, CDCl₃): δ = 2.50 (s, 6 H, 7′-CH₃, 7-CH₃), 3.68 (s, 3 H, OMe), 3.94 (s, 3 H, OMe), 3.97 (s, 3 H, OMe), 4.03 (s, 3 H, OMe), 6.61 (s, 1 H, H3′), 6.76 (d, J = 1.2 Hz, 1 H, H6′), 7.07 (s, 1 H, H3), 7.13 (d, J = 1.0 Hz, 1 H, H6), 7.50 (d, J = 1.0 Hz, 1 H, H8), 7.66 (d, J = 1.2 Hz, 1 H, H8′).

^¹³C NMR (50 MHz, CDCl₃): δ = 22.3 (CH₃), 22.4 (CH₃), 56.6 (OMe), 56.8 (OMe), 57.0 (OMe), 62.1 (OMe), 106.6 (C3′)^a, 110.1 (C6′)^a, 114.6 (C8′)^a, 117.5 (C2′)^b, 118.0 (C2)^b, 118.2 (C3)^a, 120.8 (C6)^a, 122.8 (C7′)^c, 131.4 (C7)^c, 134.7 (C4a′)^c, 137.2 (C8a′)^c, 139.6 (C8)^a, 145.2 (C4a)^d, 146.4 (C8a)^d, 147.8 (C5′)^d, 153.4 (C1′)^e, 157.4 (C4′)^e, 159.8 (C5)^e, 184.3 (C1)^f, 184.5 (C4)^f.

HRMS: m/z [M]⁺ calcd for C₂₆H₂₄O₆: 432.1572; found: 432.1546.

Anal. Calcd for C₂₆H₂₄O₆: C, 72.2; H, 5.6. Found: C, 72.0; H, 5.8.

5,5′-Dimethoxy-7,7′-dimethyl-2,2′-binaphthalene-1,1′,4,4′-tetrone (7b)

Following the typical procedure for 7a using 6b (250 mg, 0.58 mmol), MeCN (18 mL), and H₂O (8 mL) with addition of CAN (1.0 g, 1.80 mmol), MeCN (10 mL), and H₂O (10 mL) over 20 min; chromatography (EtOAc-hexane, 1:1) afforded 7b (151 mg, 65%) as yellow crystals; mp 219 ˚C (dec) (EtOAc-hexane).

IR (Nujol): 1668 (m, C=O), 1652 cm^-¹ (m, C=O).

^¹H NMR (200 MHz, CDCl₃): δ = 2.49 (s, 6 H, 7′-CH₃, 7-CH₃), 4.02 (s, 6 H, 2 OMe), 6.94 (d, J = 1.0 Hz, 2 H, H6′, H6), 7.13 (s, 2 H, H3′, H3), 7.58 (d, J = 1.0 Hz, 2 H, H8′, H8).

^¹³C NMR (50 MHz, CDCl₃): δ = 22.5 (7′-CH₃, 7-CH₃), 56.6 (2 OMe), 118.6 (C6′, C6)^a, 120.8 (C3′, C3)^a, 131.0 (C2′, C2)^b, 135.1 (C7′, C7)^b, 139.8 (C8′, C8), 141.1 (C4a′, 4a)^c, 146.9 (C8a′, 8a)^c, 160.0 (C5′, C5), 183.2 (C1′, C1)^d, 183.5 (C4′, C4)^d.

HRMS: m/z [M]⁺ calcd for C₂₄H₁₈O₆: 402.1103; found: 402.1247.

Anal. Calcd for C₂₄H₁₈O₆: C, 71.6; H, 4.5. Found: C, 71.8; H, 4.6.

2,5-Dimethoxyphenylboronic Acid (8)

Following the typical procedure for 5a using 1.32 M soln of BuLi (3.84 mL, 5.06 mmol, 1.1 equiv), 2-bromo-1,4-dimethoxybenzene (1.0g, 4.60 mmol), and THF (10 mL), but stirring the mixture for 10 min, and B(OMe)₃(2.58 mL, 2.39 g, 23.00 mmol, 5.0 equiv) with the mixture allowed to warm to 24 ˚C over 2 h. 8 (671 mg, 80%) was obtained as white crystals; mp 86-87 ˚C (benzene) (Lit. [²5] 91-93 ˚C).

IR (Nujol): 3227 (s, OH), 1503 cm^-¹ (s, Ar).

^¹H NMR (200 MHz, CDCl₃): δ = 3.81 (s, 3 H, OMe), 3.88 (s, 3 H, OMe), 6.38 [br s, 2 H, B(OH)₂], 6.85 (d, J = 8.6 Hz, 1 H, H6), 6.99 (dd, J = 8.6, 2.8 Hz, 1 H, H5), 7.39 (d, J = 2.8 Hz, 1 H, H3).

^¹³C NMR (50 MHz, CDCl₃): δ = 55.8 (OMe), 56.1 (OMe), 111.3, 118.7, 120.8 (C2, C3, C5, C6), 153.9 (C1)^a, 158.9 (C4)^a.

HRMS: m/z [M]⁺ calcd for C₈H₁₁BO₄: 182.0752; found: 182.0755.

Anal. Calcd for C₈H₁₁BO₄: C, 52.8; H, 6.1. Found: C, 52.9; H, 6.0.

2-(2,5-Dimethoxyphenyl)-7-methyl-1,4-naphthoquinone (9a)

Following the typical procedure for 6a using 2a (700 mg, 2.80 mmol), Pd(PPh₃)₄ (335 mg, 0.29 mmol), and benzene (30 mL) and aq 2 M Na₂CO₃ (3.0 mL), 8 (500 mg, 2.74 mmol), and benzene (20 mL); chromatography (EtOAc-hexane, 1:5) afforded 9a (652 mg, 76%) as reddish brown crystals; mp 63-64 ˚C (EtOH).

IR (Nujol): 1663 (s, C=O), 1655 (m, C=O), 1599 cm^-¹ (s, Ar).

^¹H NMR (200 MHz, CDCl₃): δ = 2.51 (s, 3 H, 7-CH₃), 3.74 (s, 3 H, OMe), 3.79 (s, 3 H, OMe), 6.81 (d, J = 2.6 Hz, 1 H, H3′), 6.94 (s, 1 H, H3)^a, 6.94 (m, 1 H, H6′)^a, 6.97 (m, 1 H, H5′)^a, 7.56 (dd, J = 8.2, 2.0 Hz, 1 H, H6), 7.94 (d, J = 2.0 Hz, 1 H, H8), 8.01 (d, J = 8.2 Hz, 1 H, H5).

^¹³C NMR (50 MHz, CDCl₃): δ = 21.8 (CH₃), 55.8 (OMe), 56.4 (OMe), 112.6 (C3′)^a, 115.9 (C6′)^a, 116.1 (C5′)^a, 124.4 (C2′)^b, 126.2 (C3)^c, 127.3 (C6)^c, 130.0 (C2)^b, 132.5 (C7)^b, 134.3 (C8)^c, 136.8 (C5)^c, 144.8 (C4a)^d, 147.8 (C8a)^d, 151.5 (C1′)^e, 153.5 (C4′)^e, 183.7 (C1)^f, 185.1 (C4)^f.

HRMS: m/z [M]⁺ calcd for C₁₉H₁₆O₄: 308.1048; found: 308.1049.

Anal. Calcd for C₁₉H₁₆O₄: C, 74.0; H, 5.2. Found: C, 74.2; H, 5.0.

2-(3,6-Dioxocyclohexa-1,4-dienyl)-7-methyl-1,4-naphtho­quinone (10a)

Following the typical procedure for 7a using 9a (450 mg, 1.45 mmol), MeCN (40 mL), and H₂O (16 mL) with the addition of CAN (2.4 g, 4.37 mmol), MeCN (25 mL), and H₂O (25 mL) over 20 min. Extraction was with CH₂Cl₂ (3 × 30 mL) and chromatography (EtOAc-hexane, 1:4) afforded 10a (290 mg, 71%) as yellow crystals; mp 155-157 ˚C (EtOH).

IR (Nujol): 1668 (s, C=O), 1658 (m, C=O), 1599 (s, Ar), 1580 cm^-¹ (m, Ar).

^¹H NMR (200 MHz, CDCl₃): δ = 2.52 (s, 3 H, 7-CH₃), 6.89 (br s, 3 H, H3′, H5′, H6′), 6.97 (s, 1 H, H3), 7.59 (dd, J = 8.0, 2.0 Hz, 1 H, H6), 7.92 (d, J = 2.0 Hz, 1 H, H8), 8.01(d, J = 8.0 Hz, 1 H, H5).

^¹³C NMR (50 MHz, CDCl₃): δ = 21.9 (CH₃), 126.6 (C5′)^a, 127.4 (C6′)^a, 129.8 (C2′)^b, 131.8 (C2)^b, 135.0 (C3′)^c, 135.5 (C6)^c, 136.6 (C8)^c, 136.9 (C5)^c, 138.0 (C3)^c, 141.3 (C4a)^d, 142.2 (C8a)^d, 145.6 (C7)^d, 182.9 (C1′)^e, 183.8 (C4′)^e, 184.6 (C1)^e, 186.4 (C4)^e.

HRMS: m/z [M]⁺ calcd for C₁₇H₁₀O₄: 278.0579; found: 278.0570.

Anal. Calcd for C₁₇H₁₀O₄: C, 73.4; H, 3.6. Found: C, 73.2; H, 3.8.

2-(3,6-Dioxocyclohexa-1,4-dienyl)-5-methoxy-7-methyl-1,4-naphthoquinone (9b)

Following the typical procedure for 6a using 2b (760 mg, 2.70 mmol), Pd(PPh₃)₄ (320 mg, 0.28 mmol), and benzene (30 mL) and aq 2 M Na₂CO₃ (3.0 mL), 8 (500 mg, 2.70 mmol), and benzene (20 mL); chromatography (EtOAc-hexane, 3:7) afforded 9b (575 mg, 63%) as reddish brown crystals; mp 147-149 ˚C (EtOH).

IR (Nujol): 1668 (m, C=O), 1649 (s, C=O), 1603 cm^-¹ (m, Ar).

^¹H NMR (200 MHz, CDCl₃): δ = 2.46 (s, 3 H, CH₃), 3.71 (s, 3 H, OMe), 3.77 (s, 3 H, OMe), 3.98 (s, 3 H, OMe), 6.79 (dd, J = 2.4, 0.6 Hz, 1 H, H3′), 6.86 (s, 1 H, H3), 6.90 (m, 2 H, H5′, H6′), 7.08 (d, J = 2.0 Hz, 1 H, H6), 7.58 (d, J = 2.0 Hz, 1 H, H8).

^¹³C NMR (50 MHz, CDCl₃): δ = 22.2 (CH₃), 55.7 (OMe), 56.3 (2 OMe), 112.5 (C3′)^a, 115.7 (C5′)^a, 116.0 (C6′)^a, 117.7 (C2′), 117.9 (C6)^b, 120.4 (C8)^b, 123.9 (C2)^c, 134.6 (C7)^c, 138.8 (C3)^b, 145.3 (C4a)^d, 146.1 (C8a)^d, 151.4 (C1′)^e, 153.4 (C4′)^e, 159.5 (C5)^e, 183.8 (C1)^f, 184.2 (C4)^f.

HRMS: m/z [M]⁺ calcd for C₂₀H₁₈O₅: 338.1154; found: 338.1143.

Anal. Calcd for C₂₀H₁₈O₅: C, 71.0; H, 5.4. Found: C, 71.3; H, 5.6.

2-(3,6-Dioxocyclohexa-1,4-dienyl)-5-methoxy-7-methyl-1,4-naphthoquinone (10b)

Following the typical procedure for 7a using 9a (290 mg, 0.86 mmol), MeCN (25 mL), and H₂O (10 mL) and CAN (1.44 g, 2.62 mmol), MeCN (15 mL), and H₂O (15 mL); chromatography (EtOAc-hexane, 2:3) afforded 10b (191 mg, 72%) as orange crystals; mp >300 ˚C (EtOH).

IR (Nujol): 1667 (m, C=O), 1646 (w, C=O), 1597 (w, Ar), 1577 cm^-¹ (m, Ar).

^¹H NMR (200 MHz, DMSO-d ₆): δ = 2.42 (s, 3 H, 7-CH₃), 3.90 (s, 3 H, 5-OMe), 7.03 (dd, J = 8.8, 2.6 Hz, 1 H, H5′), 7.34 (d, J = 2.0 Hz, 1 H, H6), 7.39 (d, J = 2.6 Hz, 1 H, H3′), 7.48 (s, 1 H, H3), 7.66 (d, J = 8.8 Hz, 1 H, H6′), 9.91 (d, J = 2.0 Hz, 1 H, H8).

^¹³C NMR (50 MHz, DMSO-d ₆): δ = 21.7 (CH₃), 56.3 (OMe), 106.3 (C5′)^a, 113.5 (C6′)^a, 116.7 (C2′)^b, 118.3 (C3′)^a, 119.4 (C2)^b, 119.8 (C3)^c, 120.8 (C7)^c, 122.9 (C6)^c, 134.9 (C8)^c, 146.9 (C4a)^d, 149.5 (C8a)^d, 154.7 (C5), 155.8 (C1′)^e, 160.5 (C4′)^e, 173.4 (C1)^f, 180.8 (C4)^f.

HRMS: m/z [M]⁺ calcd for C₁₈H₁₂O₅: 308.0684; found: 308.0611.

Anal. Calcd for C₁₈H₁₂O₅: C, 70.1; H, 3.9. Found: C, 70.2; H, 4.0.

2-(3,6-Dioxocyclohexa-1,4-dienyl)-5-hydroxy-7-methyl-1,4-naphthoquinone (11)

To a soln of 10b (150 mg, 0.49 mmol) in anhyd CH₂Cl₂ (20 mL) at 25 ˚C under an N₂ atmosphere was added AlCl₃ (2.61 g, 19.60 mmol). The mixture was stirred at 25 ˚C for 24 h, poured into H₂O, then acidified with dil HCl, and extracted with CH₂Cl₂. The residue obtained upon workup was chromatographed (EtOAc-hexane, 1:5) to afford 11 (78 mg, 55%) as red crystals; mp >300 ˚C (EtOAc-hexane).

IR (Nujol): 3400 (s, OH), 1650 (w, C=O), 1643 (m, C=O), 1565 cm^-¹ (w, Ar).

^¹H NMR (200 MHz, DMSO-d ₆): δ = 2.40 (s, 3 H, CH₃), 7.09 (dd, J = 9.0, 2.4 Hz, 1 H, H5′), 7.15 (d, J = 2.0 Hz, 1 H, H6), 7.43 (d, J = 2.4 Hz, 2 H, H3′, overlaid by H3), 7.72 (d, J = 9.0 Hz, 1 H, H6′), 9.97 (d, J = 2.0 Hz, 1 H, H8), 11.77 (s, 1 H, 5-OH).

^¹H NMR (200 MHz, acetone-d ₆): δ = 2.48 (s, 3 H, CH₃), 7.16 (s, 1 H, H3), 7.22 (dd, J = 9.2, 2.4 Hz, 1 H, H5′), 7.56 (d, J = 2.2 Hz, 1 H, H6), 7.62 (d, J = 2.4 Hz, 1 H, H3′), 7.68 (d, J = 9.2 Hz, 1 H, H6′), 8.93 (d, J = 2.2 Hz, 1 H, H8), 11.99 (s, 1 H, 5-OH).

^¹³C NMR (50 MHz, DMSO-d ₆): δ = 21.5 (CH₃), 106.1 (C5′)^a, 113.0 (C2′), 113.7 (C6′)^a, 119.3 (C3′)^b, 120.4 (C3)^b, 123.0 (C6)^c, 123.3 (C2)^a, 124.0 (C7)^c, 133.0 (C8), 148.4 (C4a)^d, 150.1 (C8a)^d, 153.5 (C5), 156.0 (C1′)^e, 161.4 (C4′)^e, 178.9 (C1)^f, 180.3 (C4)^f.

HRMS: m/z (M]⁺ calcd for C₁₇H₁₀O₅: 294.0528; found: 294.0571.

Anal. Calcd for C₁₇H₁₀O₅: C, 69.4; H, 3.4. Found: C, 69.2; H, 3.6.

Acknowledgment

This work was financially supported by the National Research Foundation of South Africa. The authors thank the Department of Chemistry, University of the Witwatersrand for their technical assistance in performing all the high-resolution mass spectra.

References

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References

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  CrossrefSearch in Google Scholar
• 5 Meganathan R. Vitam. Horm.  2001,  61:  173 
  PubMedSearch in Google Scholar
• 6 Kersten W. Prog. Mol. Subcell. Biol.  1971,  2:  48 
  Search in Google Scholar
• 7 Olenick CG. Hahn FE. Ann. N. Y. Acad. Sci.  1974,  235:  542 
  CrossrefPubMedSearch in Google Scholar
• 8 Pardee AB. Li YZ. Li CJ. Curr. Cancer Drug Targets  2002,  2:  227 
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  CrossrefPubMedSearch in Google Scholar
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  Search in Google Scholar
• 11 Harrison WTA. Musgrave OC. Acta. Crystallogr., Sect. C  2004,  60:  399 
  Search in Google Scholar
• 12 Yoshida M. Mori K. Eur. J. Org. Chem.  2000,  1313 
  Crossref
• 13 Lall N. Sarma MD. Hazra B. Meyer JJM. J. Antimicrob. Chemother.  2003,  51:  435 
  CrossrefPubMedSearch in Google Scholar
• 14 Adeniyi BA. Fong HHS. Pezzuto JM. Luyengi L. Odelola HA. Phytother. Res.  2000,  14:  112 
  CrossrefPubMedSearch in Google Scholar
• 15 Tran T. Saheba E. Arcerio AV. Chavez V. Li Q. Martinez LE. Primm TP. Bioorg. Med. Chem.  2004,  12:  4809 
  CrossrefPubMedSearch in Google Scholar
• 16 Alvarado PL. Avendano C. Menendez JC. Synth. Commun.  2002,  32:  3233 
  CrossrefSearch in Google Scholar
• 17a Banville J. Brassard P. J. Chem. Soc., Perkin Trans. 1  1976,  1852 
• 17b Cameron DW. Feutrill GI. Hodder DJ. J. Chem. Soc., Chem. Commun.  1978,  688 
• 17c Savard J. Brassard P. Tetrahedron Lett.  1979,  20:  4911 
  Search in Google Scholar
• 17d Cameron DW. Conn C. Feutrill GI. Aust. J. Chem.  1981,  34:  1945 
  Search in Google Scholar
• 18 Ho TI. Chen GP. Lin YC. Lin YM. Chen FC. Phytochemistry  1986,  25:  1988 
  CrossrefSearch in Google Scholar
• 19 Kesteleyn B. De Kimpe N. Puyrelde LV. J. Org. Chem.  1999,  64:  1173 
  CrossrefSearch in Google Scholar
• 20 Jung ME. Hagenah JA. J. Org. Chem.  1987,  52:  1889 
  CrossrefSearch in Google Scholar
• 21 Maddaford SP. Keay BA. J. Org. Chem.  1994,  59:  6501 
  CrossrefSearch in Google Scholar
• 22 Miyaura N. Suzuki A. Chem. Rev.  1995,  95:  2457 
  Search in Google Scholar
• 23 Syper L. Kloc K. Mlochowski J. Szulc Z. Synthesis  1979,  521 
  Thieme Connect
• 24 Inaba T. Umezawa I. Yuasa M. Inoue T. Mihashi S. ItokawaH . Ogura K. J. Org. Chem.  1987,  52:  2957 
  CrossrefSearch in Google Scholar
• 25 He Z. Craig DC. Colbran SB. J. Chem. Soc., Dalton Trans.  2002,  4224 
  Crossref