PREPARATION OF 6-SUBSTITUTED MENADIONES

Abstract

A process for the preparation of a compound having the following formula (I):

##STR00001## wherein R is selected from the group consisting of: halogen, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, and halo(C.sub.1-C.sub.6)alkoxy, said process including a step of intramolecular cyclisation, a step of bromination, a step of aromatization and a step of oxidation.

Claims

1. A process for the preparation of a compound having the following formula (I): ##STR00062## wherein R is selected from the group consisting of: halogen, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, and halo(C.sub.1-C.sub.6)alkoxy, said process comprising the following steps: a step of intramolecular cyclisation of a compound having the following formula (II): ##STR00063## R being as defined above, in order to obtain a compound having the following formula (III): ##STR00064## R being as defined above, a step of bromination of the compound having the formula (III), in order to obtain a compound having the following formula (IV): ##STR00065## R being as defined above, a step of aromatization of the compound having the formula (IV), in order to obtain a compound having the following formula (V): ##STR00066## R being as defined above, and a step of oxidation of the compound having the formula (V), in order to obtain the compound of formula (I).

2. The process of claim 1, wherein R is selected from the group consisting of: F, Br, Cl, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkyl, and halo(C.sub.1-C.sub.6)alkyl.

3. The process of claim 1, wherein R is selected from the group consisting of: F, Br, Cl, OMe, Me, and CF.sub.3.

4. The process of claim 1, wherein, when R is selected from the group consisting of: F, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, and halo(C.sub.1-C.sub.6)alkoxy, the compound of formula (II) is prepared by a process comprising the following steps: the reaction of glyoxylic acid with a compound having the following formula (VI): ##STR00067## R being as defined above, in order to obtain a compound having the following formula (VII): ##STR00068## R being as defined above, and a step of hydrogenation of the compound having the formula (VII) in order to obtain the compound having the formula (II).

5. The process of claim 1, wherein, when R is Br or Cl, the compound of formula (II) is prepared by a process comprising the following steps: the reaction of 3-methyl-3-buten-1-ol with a compound having the following formula (VIII): ##STR00069## R being as defined above, in order to obtain a compound having the following formula (IX): ##STR00070## R being as defined above, and a step of oxidation of the compound having the formula (IX) in order to obtain the compound having the formula (II).

6. The process of claim 1, wherein the intramolecular cyclisation step is carried out in acidic conditions.

7. The process of claim 1, wherein the bromination step is carried out with the addition of a brominating agent.

8. The process of claim 1, wherein the aromatization step is carried out in the presence of Li.sub.2CO.sub.3.

9. The process of claim 1, wherein the oxidation step is carried out in the presence of an oxidant selected from the group consisting of: periodic acid (H.sub.5IO.sub.6), KMnO.sub.4/H.sub.2SO.sub.4, and CrO.sub.3/H.sub.2SO.sub.4.

10. The compound having the following formula (I): ##STR00071## wherein R is selected from the group consisting of: Br, halo(C.sub.1-C.sub.6)alkyl, and halo(C.sub.1-C.sub.6)alkoxy.

11. The compound having the following formula (V): ##STR00072## wherein R is selected from the group consisting of: F, Cl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl, and halo(C.sub.1-C.sub.6)alkoxy.

12. The compound having the following formula (IV): ##STR00073## wherein R is selected from the group consisting of: F, Cl, Br, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, and halo(C.sub.1-C.sub.6)alkoxy.

13. The compound having the following formula (III): ##STR00074## wherein R is selected from the group consisting of: F, Cl, halo(C.sub.1-C.sub.6)alkyl, and halo(C.sub.1-C.sub.6)alkoxy.

14. The compound having the following formula (II): ##STR00075## wherein R is selected from the group consisting of: Cl, (C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl, and halo(C.sub.1-C.sub.6)alkoxy.

15. The compound having the following formula (VII): ##STR00076## wherein R is selected from the group consisting of: halo(C.sub.1-C.sub.6)alkyl, and halo(C.sub.1-C.sub.6)alkoxy.

16. A compound selected from the following compounds: ##STR00077## ##STR00078## ##STR00079##

17. The process according to claim 6, wherein the intramolecular cyclisation step is carried out in acidic conditions in the presence of polyphosphoric acid or trifluoroacetic anhydride/triflic acid.

18. The process according to claim 7, wherein the brominating agent is N-bromosuccinimide.

19. The compound according to claim 10, wherein R is Br or CF.sub.3.

20. The compound according to claim 11, wherein R is selected from the group consisting of: F, CF.sub.3, Cl and OMe.

21. The compound according to claim 12, wherein R is selected from the group consisting of: F, Br, Cl, CF.sub.3, Me and OMe.

22. The compound according to claim 13, wherein R is selected from the group consisting of: F, Cl and CF.sub.3.

23. The compound according to claim 14, wherein R is selected from the group consisting of: Cl, CF.sub.3 and OMe.

24. The compound according to claim 15, wherein R is CF.sub.3.

Description

EXAMPLES

Example 1: Preparation of 6-fluoromenadione

[0099] The 6-fluoromenadione is prepared according to the following reaction scheme:

##STR00020##

4-(4-fluorophenyl)-3-methyl-4-oxobut-2-enoic acid (4)

[0100] ##STR00021##

[0101] To a solution of 4-fluoropropiophenone (0.46 mL, 3.22 mmol 1 equiv.) and glyoxylic acid monohydrate (445 mg, 4.83 mmol, 1.5 equiv.) in dioxane (4.3 mL) was added dropwise sulfuric acid (0.63 mL, 11.59 mmol, 3.6 equiv.). The solution was heated to reflux for 3 hours and followed by TLC. The resulting solution was cooled to room temperature and poured into water. The mixture was extracted with Et.sub.2O, organic layer was repeatedly extracted with 10% K.sub.2CO.sub.3 aqueous solution. pH of the water layer was adjusted to acidic with a 3M HCl in water solution and extracted several times with Et.sub.2O, the organic layer was dried over MgSO.sub.4 and evaporated to dryness. The crude was dissolved in a minimal amount of toluene and crystallized using n-hexane giving a beige solid.

[0102] 83% Yield (E:Z/85:15), beige solid. .sup.1H NMR (500 MHz, Acetonitrile-d3): (*refers to the isomer Z when unambiguous distinction is possible): ? 7.89-7.84 (m, 2H), 7.48* (t, J=7.1 Hz, 0.4H), 7.26-7.19 (m, 2H), 7.15* (t, J=8.7 Hz, 0.4H), 6.08 (q, J=1.6 Hz, 1H), 5.90* (s, 0.2H), 2.32 (d, J=1.6 Hz, 3H), 1.84* (s, 0.5H). .sup.13C NMR (125 MHz, Acetonitrile-d3): (*refers to the isomer B when unambiguous distinction is possible) ? 197.4, 167.2, 166.7 (d, J=252.6 Hz), 152.8, 133.6 (d, J=9.5 Hz), 133.3* (d, J=3.0 Hz), 128.9*, 125.7, 118.3, 117.6*, 116.6 (d, J=22.3 Hz), 116.3* (d, J=21.8 Hz), 15.7, 12.5*. .sup.19F NMR (471 MHz, Acetonitrile-d3): (*refers to the isomer B when unambiguous distinction is possible) ? ?106.90-?107.05 (m), ?114.38*-?114.47* (m). HRMS (ESI): calcd. for C.sub.11H.sub.9FNaO.sub.3: 231.0428. Found: 231.0428 [MNa].sup.+.

4-(4-fluorophenyl)-3-methylbutanoic acid (4-1)

[0103] ##STR00022##

[0104] Palladium on carbon (268 mg, 0.25 mmol, 0.05 equiv.) was poured in an argon filled flask then a solution of 4-(4-fluorophenyl)-3-methyl-4-oxobut-2-enoic acid (525 mg, 2.52 mmol, 1 equiv.) in acetic acid (8.406 mL) was added to the mixture and some argon/vacuum cycles were done. Then an H.sub.2 atmosphere was created formed and the mixture was stirred during night at 70? C. under H.sub.2 atmosphere. The mixture was poured on celite, filtrated and washed using AcOH. The organic phase was evaporated giving a colorless oil which was purified on silica gel chromatography by flushing with DCM (1.5 column volume) and then EtOAc (2 column volume) to get rid of AcOH.

[0105] 91% Yield, colorless oil. .sup.1H NMR (500 MHz, Chloroform-d): ? 10.94 (s, 1H), 7.12 (dd, J=8.3, 5.3 Hz, 2H), 6.97 (t, J=8.5 Hz, 2H), 2.63 (dd, J=13.6, 6.6 Hz, 2H), 2.49 (dd, J=13.6, 7.3 Hz, 2H), 2.35 (dd, J=14.7, 5.5 Hz, 2H), 2.21 (ddd, J=35.1, 14.1, 7.3 Hz, 2H), 0.97 (d, J=6.5 Hz, 3H). .sup.13C NMR (125 MHz, Chloroform-d): 6179.9, 161.6 (d, J=243.7 Hz), 135.8 (d, J=3.3 Hz), 130.7 (d, J=7.7 Hz), 115.2 (d, J=21.1 Hz), 42.1, 40.9, 32.3, 19.6. .sup.19F NMR (471 MHz, Chloroform-d) ?: ?117.17-?117.25 (m). HRMS (ESI): calcd. for C.sub.11H.sub.12FO.sub.2: 195.0833. Found: 195.0827 (MH).

7-fluoro-3-methyl-3,4-dihydronaphthalen-1(2H)-one (5)

[0106] ##STR00023##

[0107] Polyphosphoric acid (10 mL) was first heated in a 60? C. water bath and then poured in a 100 mL flask containing 4-(4-fluorophenyl)-3-methylbutanoic acid (1 equiv., 441 mg, 2.25 mmol). The reaction mixture was stirred slowly at 90? C. After 5 minutes, the mixture turned yellow and after 1 h, the mixture was orange. The mixture was stirred overnight at 90? C. becoming dark orange. After TLC check, the mixture was poured on ice until PPA was completely dissolved by using sonicator and extracted with EtOAc (3 times). The reunited organic phases were washed with brine, dried over MgSO.sub.4 and evaporated giving a yellowish-beige oil. The oil was purified on silica gel chromatography using toluene/EtOAc (9/1) giving a yellowish oil which finally crystallizes into a yellow-beige solid.

[0108] 76% Yield, yellow-beige solid. .sup.1H NMR (500 MHz, Chloroform-d): ? 7.65 (dd, J=9.1, 2.8 Hz, 1H), 7.21 (dd, J=8.3, 5.3 Hz, 1H), 7.16 (td, J=8.3, 2.8 Hz, 1H), 2.97-2.92 (m, 1H), 2.72 (dd, J=13.0, 1.9 Hz, 1H), 2.66-2.59 (m, 1H), 2.35-2.24 (m, 2H), 1.13 (d, J=6.3 Hz, 3H). .sup.13C NMR (125 MHz, Chloroform-d): ? 197.5 (d, J=1.9 Hz), 161.6 (d, J=246.1 Hz), 139.6 (d, J=3.1 Hz), 133.9 (d, J=6.2 Hz), 130.7 (d, J=7.1 Hz), 120.9 (d, J=22.2 Hz), 113.0 (d, J=21.9 Hz), 46.8, 37.4, 30.6, 21.4. .sup.19F NMR (471 MHz, Chloroform-d): ??115.24-?115.30 (m). HRMS (ESI): calcd. for C.sub.11H.sub.12FO: 179.0867. Found: 179.0877 (MH.sup.+). M.p.=50-54? C.

2-bromo-7-fluoro-3-methyl-3,4-dihydronaphthalen-1(2H)-one (6)

[0109] ##STR00024##

[0110] A solution of 7-fluoro-3-methyl-1,2,3,4-tetrahydronaphthalen-1-one (200 mg, 1.12 mmol, 1 equiv.) in dichloromethane (0.4 mL) was added dropwise to a solution of NBS (200 mg, 1.12 mmol, 1 equiv.) and p-toluenesulfonic acid monohydrate (22 mg, 0.11 mmol, 0.1 equiv.) in dichloromethane (1.3 mL) at 0? C. The reaction mixture was then brought to reflux for 4 h. The solid dissolves gradually during the reflux. After addition of H.sub.2O, the organic layer was separated, and the aqueous layer was extracted with CH.sub.2Cl.sub.2. The combined organic layers were washed with saturated aqueous NaHCO.sub.3 and brine, dried over anhydrous MgSO.sub.4, and concentrated under reduced pressure.

[0111] 99% Brut yield, mixture of yellow oil and crystals. The product is directly used for the next step.

7-fluoro-3-methylnaphthalen-1-ol (7)

[0112] ##STR00025##

[0113] To a solution of 2-bromo-7-fluoro-3-methyl-1,2,3,4-tetrahydronaphthalen-1-one (2.3 mL, 2.3 mmol, 1 equiv.) in DMF (11.5 mL) were added lithium carbonate (187 mg, 2.53 mmol, 1.1 equiv.). The reaction mixture was stirred at 100? C. for 4.5 hours and then allowed to cool to RT. This mixture was treated with ice-cold water and extracted with diethyl ether (3 times). The combined extracts were washed with HCl (1 M), then with brine and dried (MgSO.sub.4), and concentrated in vacuum. The crude product was purified on silica gel chromatography using cyclohexane/toluene (3/7 to 100% toluene).

[0114] 71% Yield, brown-cream solid. .sup.1H NMR (400 MHz, Chloroform-d): ? 7.73 (dd, J=10.3, 2.6 Hz, 1H), 7.69 (dd, J=9.0, 5.5 Hz, 1H), 7.26-7.20 (m, 2H), 6.68 (s, 1H), 5.12 (s, 1H), 2.43 (s, 3H). .sup.13C NMR (100 MHz, Chloroform-d): ? 160.1 (d, J=243.9 Hz), 150.8 (d, J=5.3 Hz), 135.1 (d, J=2.6 Hz), 132.0, 129.4 (d, J=8.7 Hz), 123.4 (d, J=8.8 Hz), 119.8 (d, J=1.3 Hz), 116.9 (d, J=25.3 Hz), 111.7, 105.6 (d, J=22.1 Hz), 21.7. .sup.19F NMR (377 MHz, Chloroform-d): ??116.06-?116.20 (m). Elemental analysis: calcd.: 74.99% C. 5.15% H. Found: 73.61% C. 5.10% H. HRMS (ESI): calcd. for C.sub.11H.sub.8FO: 175.0570. Found: 175.0565 (MH). M.p.: 119-120? C.

6-fluoro-2-methylnaphthalene-1,4-dione (7-1)

[0115] ##STR00026##

[0116] A solution of 7-fluoro-3-methylnaphthalen-1-ol (50 mg, 0.28 mmol, 1 equiv.) in acetonitrile (3.9 mL) and water (1.4 mL) was prepared. (diacetoxyiodo)benzene (192 mg, 0.6 mmol, 2.1 equiv.) was added portion wise to the stirring solution for 20 minutes at 0? C. The mixture was stirred for 30 minutes at 0? C. then at 25? C. for 1 h. A saturated NaHCO.sub.3 solution was added to the yellow mixture and it was extracted with EtOAc. The organic phases were then washed with brine and dried over MgSO.sub.4. The organic phase has been evaporated giving a yellow solid. The crude product was purified on silica chromatography using toluene/cyclohexane (7/3).

[0117] 80% Yield, yellow solid. .sup.1H NMR (400 MHz, Chloroform-d): ? 8.15 (dd, J=8.6, 5.2 Hz, 1H), 7.71 (dd, J=8.5, 2.7 Hz, 1H), 7.38 (td, J=8.3, 2.7 Hz, 1H), 6.87 (q, J=1.6 Hz, 1H), 2.21 (d, J=1.6 Hz, 3H). .sup.13C NMR (100 MHz, Chloroform-d): ? 184.2, 183.8 (d, J=1.6 Hz), 166.0 (d, J=257.3 Hz), 148.6, 135.7 (d, J=2.0 Hz), 134.9 (d, J=7.8 Hz), 129.8 (d, J=8.9 Hz), 128.8 (d, J=3.3 Hz), 120.8 (d, J=22.5 Hz), 112.9 (d, J=23.4 Hz), 16.5. .sup.19F NMR (377 MHz, Chloroform-d): ??101.07-?103.98 (m). Elemental analysis: calcd.: 69.47% C. 3.71% H. Found: 68.98% C. 3.84% H. HRMS (ESI): calcd. for C.sub.11H.sub.8FO.sub.2:191.0509. Found: 191.0503 (MH.sup.+). M.p.=90-93? C.

Example 2: Preparation of 6-methoxymenadione

[0118] The 6-methoxymenadione is prepared according to the following reaction scheme:

##STR00027##

4-(4-methoxyphenyl)-3-methyl-4-oxobut-2-enoic acid (20)

[0119] ##STR00028##

[0120] To a solution of 4-methoxypropiophenone (2.35 g, 14.34 mmol, 1 equiv.) and glyoxylic acid monohydrate (1.98 g, 21.50 mmol, 1.5 equiv.) in 1,4-dioxane (18.6 mL) was added dropwise sulfuric acid (2.77 mL, 51.61 mmol, 3.6 equiv.). The solution was stirred for 5 h at reflux. The resulting solution was cooled to room temperature and poured into water. The reaction mixture was extracted with diethyl ether, then organic layer was washed 5 times with 10% K.sub.2CO.sub.3 aqueous solution. The pH of the aqueous layer was adjusted to acidic (pH 1) with a 3M aqueous solution of hydrochloric acid and extracted three times with diethyl ether. The organic layer was dried over MgSO.sub.4 and evaporated under reduced pressure. Dioxane was removed by a filtration on silica gel (cyclohexane then methanol) to afford the expected product as a white solid (2.79 g, 88%) as a mixture E/Z (ratio A/B, 4/1). .sup.1H NMR (CDCl.sub.3. 400 MHz): (*refers to the isomer B when unambiguous distinction is possible) ? 7.83 (d, J=8.9 Hz, 2H), 6.95 (d, J=8.9 Hz, 1.6H), 6.92* (d, J=8.9 Hz, 0.4H), 6.06 (s, 0.8H), 5.92* (s, 0.2H), 3.88 (s, 2.4H), 3.84* (s, 0.6H), 2.41 (s, 2.4H), 2.05* (0.6H). .sup.13C NMR (CDCl.sub.3, 101 MHz): (*refers to the isomer B when unambiguous distinction is possible) ? 196.5, 171.2, 164.2, 155.6*, 132.5 (2C), 128.0, 122.5, 114.2 (2C), 114.1, 55.7, 55.6*, 16.5. HRMS calculated for C.sub.12H.sub.12NaO.sub.4 [M+Na].sup.+: 243.062780. Found 243.062339.

4-(4-methoxyphenyl)-3-methylbutanoic acid (21)

[0121] ##STR00029##

[0122] Palladium on carbon (0.65 g, 0.607 mmol, 0.05 equiv.) was poured in an Argon filled flask then a solution of 20 (2.67 g, 12.13 mmol, 1 equiv.) in acetic acid (38 mL) was added and some Ar/Vacuum cycles were done. Then a H.sub.2 atmosphere was created by doing cycles H.sub.2/cycles. The mixture was stirred vigorously overnight at 70? C. under H.sub.2 atmosphere. The mixture reaction was poured on celite, filtrated and washing using acetic acid. The organic phase was evaporating to give a yellowish oil. The oil was purified by flash chromatography on silica gel (Cyclohexane, then dichloromethane, then ethyl acetate) to afford 21 as an orange oil (1.95 g, 77%). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 7.08 (d, J=8.5 Hz, 2H), 6.85-6.81 (m, 2H), 3.79 (s, 3H), 2.58 (dd, J=13.6, 6.8 Hz, 1H), 2.48 (dd, J=13.6, 7.2 Hz, 1H), 2.37 (dd, J=14.6, 5.2 Hz, 1H), 2.27-2.21 (m, 1H), 2.15 (dd, J=14.6, 8.0 Hz, 1H), 0.97 (d, J=6.5 Hz, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): 179.6, 158.1, 132.3, 130.2 (2C), 113.8 (2C), 55.4, 42.1, 40.8, 32.4, 19.7. HRMS calculated for C.sub.12H.sub.16NaO.sub.3 [M+Na].sup.+: 231.099165. Found 231.098129.

7-methoxy-3-methyl-3,4-dihydronaphthalen-1(2H)-one (21-1)

[0123] ##STR00030##

[0124] Polyphosphoric acid (40 mL) was poured in a 100 mL flask containing 21 (1.95 g, 9.36 mmol, 1 equiv.). The reaction mixture was stirred slowly overnight at 90? C. After TLC check, the mixture was poured on ice water until PPA was completely dissolved by using sonicator. Then, the aqueous phase was extracted with ethyl acetate (3 times). The reunited organic phases were washed with brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (Cyclohexane/ethyl acetate, 9/1, v/v, UV) to afford LL0022 as an orange oil (1.12 g, 63%). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 7.50 (d, J=2.8 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.05 (dd, J=8.4, 2.8 Hz, 1H), 3.83 (s, 3H), 2.94-2.89 (m, 1H), 2.73-2.70 (m, 1H), 2.64-2.58 (m, 1H), 2.24-2.31 (m, 2H), 1.13 (d, J=6.1 Hz, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 197.9, 158.1, 136.1, 132.8, 129.8, 121.4, 108.8, 55.1, 46.8, 37.0, 30.5, 21.2. HRMS calculated for C.sub.12H.sub.14NaO.sub.2 [M+Na].sup.+: 213.088600. Found 213.088658.

2-bromo-7-methoxy-3-methyl-3,4-dihydronaphthalen-1(2H)-one (22)

[0125] ##STR00031##

[0126] A solution of 21 (1.12 g, 5.89 mmol, 1 equiv.) in dichloromethane (2.01 mL) was added dropwise to a solution of N-bromosuccinimide (1.05 g, 5.89 mmol, 1 equiv.) and p-toluenesulfonic acid monohydrate (0.11 g, 0.59 mmol, 0.1 equiv.) in dichloromethane (6.6 mL) at 0? C. The reaction mixture was stirred at reflux for 3.5 h. After addition of water, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous NaHCO.sub.3 and brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (Toluene, UV) to afford 22 as an orange oil and mixture of isomers (1.58 g, quant.). .sup.1H NMR (CDCl.sub.3, 400 MHz): (*refers to the isomer B when unambiguous distinction is possible) ? 7.55 (d, J=2.8 Hz, 0.55H), 7.53* (d, J=2.8 Hz, 0.45H), 7.17* (s, 0.35H), 7.15 (s, 0.65H), 7.14-7.06 (m, 1H), 4.53 (dd, J=2.6, 1.2 Hz, 0.55H), 4.45-4.43* (m, 0.45H), 3.83 (s, 3H), 3.37* (dd, J=16.4, 4.2 Hz, 0.45H), 2.86 (ddd, J=16.9, 10.7, 1.0 Hz, 0.55H), 2.75-2.56 (m, 2H), 2.30-2.19 (m, 0.7H), 1.21 (d, J=6.4 Hz, 1.65H), 1.20 (d, J=6.8 Hz, 1.35H). .sup.13C NMR (CDCl.sub.3, 101 MHz): (*refers to the isomer B when unambiguous distinction is possible) ? 191.2, 190.7*, 158.7, 135.6, 133.9*, 130.7*, 130.5, 130.2*, 130.0, 123.0*, 122.9, 110.3, 110.1*, 58.8, 56.7*, 55.6, 37.6*, 35.0, 33.4*, 32.8, 19.2*, 19.1. HRMS calculated for C.sub.12H.sub.14BrO.sub.2 [M+H].sup.+: 269.017168. Found 269.016447.

7-methoxy-3-methylnaphthalen-1-ol (23)

[0127] ##STR00032##

[0128] To a solution of 22 (1.58 g, 5.86 mmol, 1 equiv.) in dimethylformamide (29.3 mL) was added lithium carbonate (0.48 g, 6.45 mmol, 1.1 equiv.). The reaction mixture was stirred at 100? C. for 4.5 hours and then allowed to cool to room temperature. This reaction mixture was treated with ice-cold water and extracted with diethyl ether (3?). The combined extracts were washed a 1M solution of HCl, then with brine, dried over MgSO.sub.4, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel (Toluene/Cyclohexane, gradient from 9/1 to 1/0 then Toluene/ethyl acetate, 9/1, v/v, UV) to afford 23 as a white solid (49 mg, 73%). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 7.63 (d, J=9.0 Hz, 1H), 7.43 (d, J=2.6 Hz, 1H), 7.17 (q, J=1.1 Hz, 1H), 7.15 (dd, J=8.9, 2.6 Hz, 1H), 5.27 (s, 1H), 3.94 (s, 3H), 2.42 (s, 4H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 156.9, 150.4, 133.3, 130.6, 128.8, 123.5, 119.8, 119.4, 111.5, 100.0, 55.5, 21.6. HRMS calculated for C.sub.12H.sub.13O [M+H].sup.+: 189.091006. Found 189.091766. M.p.=92-95? C.

6-methoxy-2-methylnaphthalene-1,4-dione (23-1)

[0129] ##STR00033##

[0130] A solution of 23 (890 mg, 4.73 mmol, 1 equiv.) in a mixture of acetonitrile (65.6 mL) and water (23.0 mL) was prepared. At 0? C., (diacetoxyiodo)benzene (3.2 g, 9.93 mmol, 2.1 equiv.) was added portionwise to the stirring solution. The mixture reaction was stirred for 30 minutes at 0? C. then at room temperature for 1 h. A saturated aqueous solution of NaHCO.sub.3 was added to the yellow mixture and it was extracted with ethyl acetate. The organic phases were washed with brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel (Toluene/ethyl acetate, gradient from 1/0 to 9/1, v/v, UV) to give a yellow solid (328 mg, 35%). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.04 (d, J=8.6 Hz, 1H), 7.49 (d, J=2.7 Hz, 1H), 7.18 (dd, J=8.7, 2.7 Hz, 1H), 6.79 (q, J=1.6 Hz, 1H), 3.94 (s, 3H), 2.18 (d, J=1.6 Hz, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 185.2, 184.7, 164.1, 148.6, 135.4, 134.5, 129.2, 125.9, 120.4, 109.4, 56.0, 16.6. M.p.=150-153? C.

Example 3: Preparation of 6-methylmenadione

[0131] The 6-methylmenadione is prepared according to the following reaction scheme:

##STR00034##

4-(4-methylphenyl)-3-methyl-4-oxobut-2-enoic acid (25)

[0132] ##STR00035##

[0133] To a solution of 4-methylpropiophenone (2 g, 13.49 mmol, 1 equiv.) and glyoxylic acid monohydrate (1.86 g, 20.24 mmol, 1.5 equiv.) in 1,4-dioxane (17.5 mL) was added dropwise sulfuric acid (2.6 mL, 48.58 mmol, 3.6 equiv.). The solution was stirred for 5 h at reflux. The resulting solution was cooled to room temperature and poured into water. The reaction mixture was extracted with diethyl ether, then organic layer was washed 5 times with 10% K.sub.2CO.sub.3 aqueous solution. The pH of the aqueous layer was adjusted to acidic (pH 1) with a 3M aqueous solution of hydrochloric acid and extracted three times with diethyl ether. The organic layer was dried over MgSO.sub.4 and evaporated under reduced pressure to afford the expected product, without further purification, as a white solid (2.74 g, 99%) as a mixture E/Z. .sup.1H NMR (CDCl.sub.3, 400 MHz): (*refers to the isomer B when unambiguous distinction is possible) ? 7.70 (d, J=8.1 Hz, 1.2H), 7.49* (br s, 0.8H), 7.25 (d, J=8.4 Hz, 1.2H), 7.20* (d, J=8.0 Hz, 0.8H), 6.09 (s, 0.6H), 5.87* (s, 0.4H), 2.41 (s, 1.8H), 2.36 (s, 3H), 1.98* (s, 1.2H). .sup.13C NMR (CDCl.sub.3, 101 MHz): (*refers to the isomer B when unambiguous distinction is possible) ? 197.7, 171.4, 144.6, 132.9, 130.1 (2C), 129.6, 129.5 (2C), 117.4, 21.8, 21.5*, 16.1. HRMS calculated for C.sub.12H.sub.12NaO.sub.3 [M+Na].sup.+: 227.067865. Found 227.068137.

4-(4-methylphenyl)-3-methylbutanoic acid (26)

[0134] ##STR00036##

[0135] Palladium on carbon (0.69 g, 0.65 mmol, 0.05 equiv.) was poured in an Argon filled flask then a solution of 25 (2.64 g, 12.93 mmol, 1 equiv.) in acetic acid (40.5 mL) was OH added and some Ar/Vacuum cycles were done. Then a H.sub.2 atmosphere was created by doing cycles H.sub.2/cycles. The mixture was stirred vigorously overnight at 70? C. under H.sub.2 atmosphere. The mixture reaction was poured on celite, filtrated and washing using acetic acid. The organic phase was evaporating to give a yellowish oil. The oil was purified by flash chromatography on silica gel (Cyclohexane, then dichloromethane, then ethyl acetate) to afford 26 as a yellowish oil (2.38 g, 96%). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 7.10 (d, J=8.0 Hz, 2H), 7.06 (d, J=8.1 Hz, 2H), 2.61 (dd, J=13.5, 6.8 Hz, 1H), 2.50 (dd, J=13.5, 7.3 Hz, 1H), 2.38 (dd, J=14.8, 5.4 Hz, 1H), 2.33 (s, 3H), 2.27 (dt, J=13.3, 6.8 Hz, 1H), 2.17 (dd, J=14.8, 8.1 Hz, 1H), 0.99 (d, J=6.5 Hz, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 179.7, 137.1, 135.7, 129.2 (2C), 129.1 (2C), 42.6, 40.9, 32.3, 21.1, 19.7. HRMS calculated for C.sub.12H.sub.16NaO.sub.2 [M+Na].sup.+: 215.104250. Found 215.104381.

7-methyl-3-methyl-3,4-dihydronaphthalen-1(2H)-one (27)

[0136] ##STR00037##

[0137] Polyphosphoric acid (30 mL) was poured in a 100 mL flask containing 26 (2.3 g, 11.70 mmol, 1 equiv.). The reaction mixture was stirred slowly overnight at 90? C. After TLC check, the mixture was poured on ice water until PPA was completely dissolved by using sonicator. Then, the aqueous phase was extracted with ethyl acetate (3 times). The reunited organic phases were washed with brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (Toluene/ethyl acetate, 8/2, v/v) to afford 27 as a white solid (1.58 g, 77%). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 7.81 (s, 1H), 7.27 (dd, J=7.5, 2.0 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H), 2.97-2.86 (m, 1H), 2.69 (dd, J=12.8, 1.9 Hz, 1H), 2.61 (dd, J=16.4, 10.5 Hz, 1H), 2.34 (s, 3H), 2.31-2.21 (m, 2H), 1.11 (d, J=6.2 Hz, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 198.8, 141.0, 136.3, 134.5, 132.0, 128.8, 127.1, 47.3, 37.7, 30.7, 21.4, 21.0. HRMS calculated for C.sub.12H.sub.14NaO [M+Na].sup.+: 197.093686. Found 197.094299. M.p.=47-48? C.

2-bromo-7-methyl-3-methyl-3,4-dihydronaphthalen-1(2H)-one (24)

[0138] ##STR00038##

[0139] A solution of 27 (150 mg, 0.86 mmol, 1 equiv.) in dichloromethane (0.31 mL) was added dropwise to a solution of N-bromosuccinimide (153.2 mg, 0.86 mmol, 1 equiv.) and p-toluenesulfonic acid monohydrate (16.6 mg, 0.086 mmol, 0.1 equiv.) in dichloromethane (0.96 mL) at 0? C. The reaction mixture was stirred at reflux for 3.5 h. After addition of water, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous NaHCO.sub.3 and brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (Toluene/cyclohexane, 4/6, UV) to afford 24 as an orange oil and mixture of isomers (210 mg, 96%). .sup.1H NMR (CDCl.sub.3, 400 MHz): (*refers to the isomer B when unambiguous distinction is possible) ? 7.90-7.87 (m, 1H), 7.36-7.32 (m, 1H), 7.15 (m, 1H), 4.53 (dd, J=2.7, 1.4 Hz, 0.7H), 4.44* (m, 0.3H), 3.40* (dd, 0.3H, J=16.8, 4.5 Hz), 2.90 (m, 0.70H), 2.72 (m, 1H), 2.62* (m, 0.3H), 2.37 (s, 3H), 2.25 (m, 0.7H), 1.22-1.20 (m, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): (*refers to the isomer B when unambiguous distinction is possible) ? 191.3, 190.8*, 140.0, 138.4*, 136.8, 135.5*, 135.2, 129.6*, 129.1*, 129.1, 128.7, 128.7, 128.3*, 128.2*, 59.1, 57.0*, 37.4*, 34.7, 33.7*, 33.1, 21.8*, 21.0, 19.2*, 19.1. HRMS calculated for C.sub.12H.sub.13BrNaO [M+Na].sup.+: 275.004198. Found 275.004086.

7-methyl-3-methylnaphthalen-1-ol (28)

[0140] ##STR00039##

[0141] To a solution of 24 (2.32 g, 9.18 mmol, 1 eq) in dimethylformamide (54.7 mL) was added lithium carbonate (0.75 g, 10.09 mmol, 1.1 equiv.). The reaction mixture was stirred at 100? C. for 4.5 h and then allowed to cool to room temperature. This reaction mixture was treated with ice-cold water and extracted with diethyl ether (3?). The combined extracts were washed a 1M solution of HCl, then with brine, dried over MgSO.sub.4, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel (Toluene, UV) to afford 28 as a brown solid (971 mg, 61%). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 7.86 (s, 1H), 7.62 (d, J=8.3 Hz, 1H), 7.29 (dd, J=8.4, 1.8 Hz, 1H), 7.18 (s, 1H), 6.64 (d, J=1.7 Hz, 1H), 5.04 (m, 1H), 2.51 (s, 3H), 2.43 (s, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 150.7, 134.9, 134.2, 133.3, 128.9, 127.1, 122.8, 120.3, 119.8, 111.0, 21.9, 21.8. HRMS calculated for C.sub.12H.sub.13O [M+H].sup.+: 173.096091. Found 173.096314. M.p.=93-96? C.

6-methyl-2-methylnaphthalene-1,4-dione (29)

[0142] ##STR00040##

[0143] A solution of 28 (970 mg, 5.64 mmol, 1 equiv.) in a mixture of acetonitrile (115.2 mL) and water (35.2 mL) was prepared. At 0? C. (diacetoxyiodo)benzene (2.18 g, 6.77 mmol, 2.1 equiv.) was added portionwise to the stirring solution. The mixture reaction was stirred for 30 minutes at 0? C. then at room temperature for 1 h. A saturated aqueous solution of NaHCO.sub.3 was added to the yellow mixture and it was extracted with ethyl acetate. The organic phases were washed with brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel (Toluene/Cyclohexane, 8/2, v/v, UV) to give a yellow solid (857 mg, 82%). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 7.98 (d, J=7.9 Hz, 1H), 7.85 (dd, J=1.2, 0.6 Hz, 1H), 7.50 (ddd, J=8.0, 1.8, 0.9 Hz, 1H), 6.79 (q, J=1.6 Hz, 1H), 2.48 (s, 3H), 2.18 (d, J=1.6 Hz, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 185.5, 185.4, 148.3, 144.9, 135.6, 134.4, 132.3, 130.1, 126.8, 126.5, 21.9, 16.6. HRMS calculated for C.sub.12H.sub.11O.sub.2 [M+H].sup.+: 187.075356. Found 187.076313. M.p.=130-132? C.

Example 4: Preparation of 6-trifluoromenadione

[0144] The 6-trifluoromenadione is prepared according to the following reaction scheme:

##STR00041##

4-(4-trifluorophenyl)-3-methyl-4-oxobut-2-enoic acid (8)

[0145] ##STR00042##

[0146] To a solution of 4-trifluoromethylpropiophenone (5 g, 24.73 mmol, 1 equiv.) and glyoxylic acid monohydrate (2.75 g, 37.09 mmol, 1.5 equiv.) in 1,4-dioxane (31.6 mL) was added dropwise sulfuric acid (4.77 mL, 89.03 mmol, 3.6 equiv.). The solution was stirred for 4 h at reflux. The resulting solution was cooled to room temperature and poured into water. The reaction mixture was extracted with diethyl ether, then organic layer was washed 5 times with 10% K.sub.2CO.sub.3 aqueous solution. The pH of the aqueous layer was adjusted to acidic (pH 1) with a 3M aqueous solution of hydrochloric acid and extracted three times with diethyl ether. The organic layer was dried over MgSO.sub.4 and evaporated under reduced pressure to afford the expected product, without further purification, as a white solid (4.29 g, 67%) as a mixture E/Z (ratio A/B, 4/1, *refers to the isomer B when unambiguous distinction is possible). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 11.34 (br s, 1H), 7.89 (d, AB syst, J=8.0 Hz, 2H), 7.74 (d, AB syst, J=8.1 Hz, 2H), 7.66-7.58* (m, 1H), 6.17 (d, J=1.6 Hz, 1H), 5.88* (s, 0.25H), 2.43 (s, 3H), 1.92* (s, 0.75H). .sup.19F NMR (377 MHz, CDCl.sub.3): ? ?62.86*, ?63.24. .sup.13C NMR (101 MHz, CDCl.sub.3): ? 196.8, 171.9*, 170.0, 168.8*, 153.7, 140.2*, 138.7, 134.8 (q, .sup.2J.sub.C-F=32.8 Hz), 131.8* (q, .sup.2J.sub.C-F=32.9 Hz), 130.1 (2C), 127.6*, 126.4*, 125.8 (q, .sup.3J.sub.C-F=3.7 Hz, 2C), 125.6*, 123.9 (d, .sup.1J.sub.C-F=272.7 Hz), 123.5 (d, .sup.1J.sub.C-F=272.8 Hz), 119.5*, 117.0, 106.9*, 15.7, 12.6*. HRMS (ESI+): calculated for C.sub.12H.sub.9F.sub.3NaO.sub.3 [M+Na].sup.+: 281.039600. Found 281.039775.

4-(4-trifluorophenyl)-3-methylbutanoic acid (9)

[0147] ##STR00043##

[0148] Palladium on carbon (0.83 g, 0.78 mmol, 0.05 equiv.) was poured in an Argon filled flask then a solution of 8 (4.04 g, 15.65 mmol, 1 equiv.) in acetic acid (60.9 mL) was added and some Ar/Vacuum cycles were done. Then a H.sub.2 atmosphere was created by doing cycles H.sub.2/cycles. The mixture was stirred vigorously overnight at 70? C. under H.sub.2 atmosphere. The mixture reaction was poured on celite, filtrated and washing using acetic acid. The organic phase was evaporating to give 9, without further purification, as a yellowish oil (3.81 g, 99%). .sup.1H NMR (400 MHz, CDCl.sub.3): ? 11.97 (s, 1H), 7.56 (d, AB syst, J=7.9 Hz, 2H), 7.30 (d, AB syst, J=7.9 Hz, 2H), 2.75 (dd, J=13.5, 6.0 Hz, 1H), 2.59 (dd, J=13.5, 7.1 Hz, 1H), 2.43-2.29 (m, 2H), 2.24 (dd, J=13.9, 6.4 Hz, 1H), 1.01 (d, J=6.2 Hz, 3H). .sup.19F NMR (377 MHz, CDCl.sub.3): ? ?62.34. .sup.13C NMR (101 MHz, CDCl.sub.3): ? 179.9, 144.4, 129.6 (2C), 128.7 (q, .sup.2J.sub.C-F=33.3 Hz), 125.4 (d, .sup.3J.sub.C-F=3.7 Hz, 2C), 124.5 (q, .sup.1J.sub.C-F=271.8 Hz), 42.7, 40.9, 32.0, 19.6. HRMS (ESI+): calculated for C.sub.12H.sub.14F.sub.3O.sub.2 [M+H].sup.+: 247.094041. Found 247.093769.

7-trifluoro-3-methyl-3,4-dihydronaphthalen-1(2H)-one (10)

[0149] ##STR00044##

[0150] In a round bottom flask, the acid 9 (3.43 g, 13.93 mmol, 1 equiv.) was dissolved in dichloromethane (34 mL) then TFAA (11.62 mL, 83.58 mmol, 6 equiv.) was added followed by triflic acid (1.86 mL, 20.89 mmol, 1.5 equiv.). The mixture reaction was stirred for 1 h. After this time, the mixture was treated with water and extracted with dichloromethane. The organic phase was washed with a saturated aqueous solution of NaHCO.sub.3, dried over MgSO.sub.4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel (Toluene/Ethyl acetate, 8/2, v/v, UV) to afford the expected product 10 as a white solid (3.04 g, 95%). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.27 (s, 1H), 7.68 (dd, J=8.0, 2.0 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 3.03 (br d, 1H, J=17.5 Hz), 2.78-2.69 (m, 2H), 2.39-2.32 (m, 2H), 1.16 (2d, 3H, J=6.3 Hz). .sup.19F NMR (377 MHz, CDCl.sub.3): ? ?62.7. .sup.13C NMR (101 MHz, CDCl.sub.3): ? 197.2, 147.4, 132.6, 129.8, 129.7 (q, .sup.3J.sub.C-F=3.6 Hz), 129.3, 124.3 (q, .sup.3J.sub.C-F=3.6 Hz), 124.0 (d, .sup.1J.sub.C-F=272.2 Hz), 46.9, 37.9, 30.3, 21.3. HRMS (ESI+): calculated for C.sub.12H.sub.12F.sub.3O [M+H].sup.+: 229.083476. Found 229.073453. M.p.: 55-58? C.

2-bromo-7-trifluoro-3-methyl-3,4-dihydronaphthalen-1(2H)-one (11)

[0151] ##STR00045##

[0152] A solution of 10 (609 mg, 2.67 mmol, 1 equiv.) in dichloromethane (1.2 mL) was added dropwise to a solution of N-bromosuccinimide (570.0 mg, 3.2 mmol, 1 equiv.) and p-toluenesulfonic acid monohydrate (51.5 mg, 0.27 mmol, 0.1 equiv.) in dichloromethane (3.1 mL) at 0? C. The reaction mixture was stirred at reflux for 3.5 h. After addition of water, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous NaHCO.sub.3 and brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (Toluene/cyclohexane, 7/3, v/v, UV) to afford 11 as a yellowish oil (576 mg, 70%) and mixture of isomers (mixture A/B (ratio 1.8/1, *refers to the isomer B when unambiguous distinction is possible). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.34 (2s, 1H), 7.74 (m, 1H), 7.41 (d, J=7.8 Hz, 0.35H), 7.40 (d, J=8.1 Hz, 0.65H), 4.56 (br s, 0.65H), 4.46* (d, J=5.9 Hz, 0.35H), 3.52* (dd, J=17.4, 4.6 Hz, 0.35H), 2.99 (dd, J=17.5, 10.8 Hz, 0.65H), 2.83 (2dd, J=16.9, 11.5 Hz, 1H), 2.70-2.64* (m, 0.35H), 2.33-2.27 (m, 0.65H), 1.24 (d, J=6.4 Hz, 1.95H), 1.20* (d, J=7.0 Hz, 1.05H). .sup.19F NMR (377 MHz, CDCl.sub.3): ? ?62.83. .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 189.9, 189.5*, 146.4, 144.8*, 130.5* (q, .sup.3J.sub.C-F=3.7 Hz), 130.3*, 130.2 (q, .sup.3J.sub.C-F=3.6 Hz), 130.0, 129.8, 129.7, 125.9 (d, .sup.3J.sub.C-F=4.2 Hz), 125.5* (d, .sup.3J.sub.C-F=3.6 Hz), 123.7 (q, .sup.1J.sub.C-F=272.3 Hz), 58.0, 55.2*, 36.8*, 34.3, 33.6*, 33.4, 18.9, 18.8*. HRMS (ESI+): calculated for C.sub.12H.sub.11BrF.sub.3O [M+H].sup.+: 306.993988. Found 306.993449.

7-trifluoro-3-methylnaphthalen-1-ol (12)

[0153] ##STR00046##

[0154] To a solution of 11 (477.8 mg, 1.56 mmol, 1 equiv.) in dimethylformamide (9.3 mL) was added lithium carbonate (126.5 g, 1.71 mmol, 1.1 equiv.). The reaction mixture was stirred at 100? C. for 4.5 h and then allowed to cool to room temperature. This reaction mixture was treated with ice-cold water and extracted with diethyl ether (3?). The combined extracts were washed a 1M solution of HCl, then with brine, dried over MgSO.sub.4, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel (Toluene/cyclohexane, 7/3, v/v, UV) to afford 12 as a brown solid (319 mg, 91%). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.48 (s, 1H), 7.79 (d, AB syst, J=8.6 Hz, 1H), 7.60 (dd, AB syst, J=8.7, 1.9 Hz, 1H), 7.25 (s, 1H), 6.71 (s, 1H), 5.43 (s, 1H), 2.46 (s, 3H). .sup.19F NMR (377 MHz, CDCl.sub.3): ? ?62.02. .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 151.9, 138.8, 136.1, 128.0, 126.3 (d, .sup.2J.sub.C-F=33.3 Hz), 124.8 (d, .sup.1J.sub.C-F=273.7 Hz), 122.2 (q, .sup.3J.sub.C-F=3.2 Hz), 121.7, 120.1 (q, .sup.3J.sub.C-F=4.5 Hz), 119.8, 112.0, 22.0. HRMS (ESI+): calculated for C.sub.12H.sub.10F.sub.3O [M+H].sup.+: 227.067826. Found 227.067355. M.p.: 88-91? C.

7-trifluoro-3-methylnaphthalen-1-ol (1)

[0155] ##STR00047##

[0156] A solution of 12 (2.45 g, 10.83 mmol, 1 equiv.) in a mixture of acetonitrile (192.9 mL) and water (67.7 mL) was prepared. At 0? C., (diacetoxyiodo)benzene (4.19 g, 13.0 mmol, 2.1 equiv.) was added portionwise to the stirring solution. The mixture reaction was stirred for 30 minutes at ?5? C. A saturated aqueous solution of NaHCO.sub.3 was added to the yellow mixture and it was extracted with ethyl acetate. The organic phases were washed with brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel (Toluene/Cyclohexane, 6/4, v/v, UV) to give a yellow solid (1.54 g, 59%). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.33, 8.24 (d, AB syst, J=8.1 Hz, 2H), 7.98 (dd, AB syst, J=8.1, 1.8 Hz, 1H), 6.93 (q, J=1.6 Hz, 1H), 2.23 (d, J=1.5 Hz, 3H). .sup.19F NMR (377 MHz, CDCl.sub.3): ? ?63.38. .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 184.5, 183.6, 148.8, 136.0, 135.4 (d, .sup.2J.sub.C-F=33.3 Hz), 134.3, 132.7, 130.0 (q, .sup.3J.sub.C-F=3.7 Hz), 127.4, 123.5 (q, .sup.3J.sub.C-F=3.9 Hz), 123.3 (d, .sup.1J.sub.C-F=273.3 Hz), 16.6. HRMS (ESI+): calculated for C.sub.12H.sub.8F.sub.3O.sub.2[M+H].sup.+: 241.047091. Found 241.046381. M.p.: 97-99? C.

Example 5: Preparation of 6-bromomenadione

[0157] The 6-bromomenadione is prepared according to the following reaction scheme:

##STR00048##

4-(4-bromophenyl)-3-methyl-4-oxobut-2-enoic acid (13)

[0158] ##STR00049##

[0159] To a solution of 4-bromopropiophenone (2 g, 9.39 mmol, 1 equiv.) and glyoxylic acid monohydrate (1.3 g, 14.08 mmol, 1.5 equiv.) in dioxane (12.2 mL) was added dropwise sulfuric acid (1.81 mL, 33.79 mmol, 3.6 equiv.). The solution was stirred overnight at reflux. The resulting solution was cooled to room temperature and poured into water. The reaction mixture was extracted with diethyl ether, then organic layer was washed 5 times with 10% K.sub.2CO.sub.3 aqueous solution. The pH of the aqueous layer was adjusted to acidic (pH 1) with a 3M aqueous solution of hydrochloric acid and extracted three times with diethyl ether. The organic layer was dried over MgSO.sub.4 and evaporated under reduced pressure. Dioxane was removed by a filtration on silica gel (cyclohexane then methanol) to afford the expected product as a white solid (2.27 g, 90%) as a mixture E/Z (ratio A/B, 4/1). .sup.1H NMR (CDCl.sub.3, 400 MHz): (*refers to the isomer B when unambiguous distinction is possible) ? 7.67 (d, AB syst, J=8.6 Hz, 2H), 7.62 (d, AB syst, J=8.6 Hz, 2H), 7.52* (d, AB syst, J=8.6 Hz, 0.4H), 7.34* (d, AB syst, J=8.5 Hz, 0.4H), 6.15 (br d, J=1.4 Hz, 1H), 5.86* (br d, J=1.0 Hz, 0.2H), 2.42 (d, J=1.3 Hz, 3H), 1.91* (d, J=0.8 Hz, 0.6H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? (*refers to the isomer B when unambiguous distinction is possible) 196.8, 171.0, 168.6*, 154.3, 135.5*, 134.2, 132.2 (2C), 132.0*, 131.4 (2C), 130.3*, 129.0*, 127.6, 124.3*, 116.8, 106.8*, 16.1, 12.6*. HRMS calculated for C.sub.11H.sub.9BrNaO.sub.3 [M+Na].sup.+: 290.962727. Found 290.963532.

4-(4-bromophenyl)-3-methylbutanoic acid (30)

[0160] ##STR00050##

[0161] 30 was synthetized according to Sleebs procedure (Sleebs, B. E.; Kersten, W. J. A.; Kulasegaram, S.; Nikolakopoulos, G.; Hatzis, E.; Moss R. M.; Parisot, J. P.; Yang, H.; Czabotar, P. E.; Fairlie, W. D.; Lee, E. F.; Adams, J. M.; Chen, L; Van Delft, M. F.; Lowes, K. N., Wei, A.; Huang, D. C. S.; Colman, P. M.; Street, I. P.; Baell, J. B.; Watson, K.; Lessene, G. J. Med. Chem. 2013, 59, 5514-5540). A mixture of 1-bromo-4-iodobenzene (10.0 g, 35.35 mmol, 1 equiv.), lithium acetate (5.8 g, 87.97 mmol, 2.49 equiv.), lithium chloride (1.5 g, 35.39 mmol, 1 equiv.), 3-methyl-3-buten-1-ol (3.6 mL, 35.35 mmol, 1 equiv.), tetrabutylammonium chloride hydrate (21.0 g, 70.77 mmol, 2 equiv.) and palladium diacetate (0.45 g, 2 mmol, 0.057 equiv.) in dimethylformamide (68 mL) was stirred at 70? C. for 72 h. After this time, the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride. Then, the reaction mixture was extracted three times with diethyl ether. The combined organic layers were washed with brine, dried over MgSO.sub.4 and concentrated under reduced pressure. No further purification was required and the product was used in the next step directly. 280 mL of acetonitrile was added to periodic acid (8.1 g, 35.46 mmol, 1.09 equiv.) and the resulting mixture was stirred for 15 min. At 0? C., a solution of 4-(4-bromophenyl)-3-methylbutanal (7.9 g, 32.68 mmol, 1 equiv.) in acetonitrile (35 mL) was added followed by pyridinium chlorochromate (0.14 g, 0.65 mmol, 0.02 equiv.) in 35 mL of acetonitrile. The reaction mixture was then stirred at room temperature for 3.5 h. After this time, ethyl acetate was added. The organic phase was washed with a 1:1 water/brine mixture, a saturated aqueous of sodium hydrogen sulfate solution and brine. It was then dried over MgSO.sub.4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (Dichloromethane/methanol, gradient from 98/2 to 95/5, v/v, UV) to afford 30 as an oil. .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 7.44-7.37 (m, 2H), 7.04 (d, J=8.3 Hz, 2H), 2.62 (dd, J=13.5, 6.4 Hz, 1H), 2.47 (dd, J=13.5, 7.3 Hz, 1H), 2.35 (dd, J=14.3, 5.2 Hz, 1H), 2.30-2.15 (m, 3H), 0.97 (d, J=6.4 Hz, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 179.2, 139.1, 131.5 (2C), 131.1 (2C), 120.1, 42.3, 40.7, 32.1, 19.6. HRMS calculated for C.sub.11H.sub.12BrO.sub.2 [M?H].sup.?: 255.002615. Found 255.001185.

7-bromo-3-methyl-3,4-dihydronaphthalen-1(2H)-one (31)

[0162] ##STR00051##

[0163] Polyphosphoric acid (80 mL) was poured in a 250 mL flask containing 30 (5.46 g, 21.23 mmol, 1 equiv.). The reaction mixture was stirred slowly overnight at 90? C. After TLC check, the mixture was poured on ice water until PPA was completely dissolved by using sonicator. Then, the aqueous phase was extracted with ethyl acetate (3 times). The reunited organic phases were washed with brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (Toluene/ethyl acetate, 8/2, v/v, UV) to afford 31 as a white solid (4.47 g, 88%). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.11 (d, J=2.2 Hz, 1H), 7.55 (dd, J=8.2, 2.2 Hz, 1H), 7.12 (d, J=8.2 Hz, 1H), 2.92 (dd, J=16.3, 3.6 Hz, 1H), 2.71 (dd, J=13.0, 1.8 Hz, 1H), 2.60 (dd, J=16.3, 10.0 Hz, 1H), 2.34-2.25 (m, 2H), 1.13 (d, J=6.2 Hz, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 197.2, 142.5, 136.3, 133.8, 130.8, 129.9, 120.7, 46.9, 37.5, 30.4, 21.4. HRMS calculated for C.sub.11H.sub.12BrO [M+H].sup.+: 239.006604. Found 239.006402. M.p.=59-61? C.

2-bromo-7-bromo-3-methyl-3,4-dihydronaphthalen-1(2H)-one (14)

[0164] ##STR00052##

[0165] A solution of 31 (96 mg, 0.401 mmol, 1 equiv.) in dichloromethane (0.14 mL) was added dropwise to a solution of N-bromosuccinimide (71.5 mg, 0.401 mmol, 1 equiv.) and p-toluenesulfonic acid monohydrate (7.75 mg, 0.040 mmol, 0.1 equiv.) in dichloromethane (0.45 mL) at 0? C. The reaction mixture was stirred at reflux for 3.5 h. After addition of water, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous NaHCO.sub.3 and brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (Toluene/cyclohexane, 8/2, v/v, UV) to afford 14 as yellowish oil and mixture of isomers (ratio A/B: 1.6/1, 103 mg, 81%). .sup.1H NMR (CDCl.sub.3, 400 MHz): (*refers to the isomer B when unambiguous distinction is possible) ? 8.17 (d, J=2.2 Hz, 0.6H), 8.16* (d, J=2.2 Hz, 0.4H), 7.60 (td, J=8.2, 2.2 Hz, 1H), 7.14 (dd, J=8.1, 3.5 Hz, 1H), 4.50 (br dd, J=2.4, 0.8 Hz, 0.6H), 4.42* (d, J=8.0 Hz, 0.4H), 3.38* (dd, J=16.8, 4.0 Hz, 0.4H), 2.86 (m, 1H), 2.76-2.51 (m, 1.4H), 2.25 (dtdq, J=10.6, 6.4, 3.8, 2.3, 1.8 Hz, 0.6H), 1.21 (d, J=6.5 Hz, 1.8H), 1.18* (d, J=6.9 Hz, 1.2H). .sup.13C NMR (CDCl.sub.3, 101 MHz): (*refers to the isomer B when unambiguous distinction is possible) ? 189.8, 189.4*, 141.5, 139.9*, 137.2*, 136.9, 131.34, 131.28*, 131.1*, 130.98*, 130.95, 130.6, 121.1, 58.1, 58.6*, 36.9*, 34.4, 33.4*, 33.0, 19.0. HRMS calculated for C.sub.11H.sub.11Br.sub.2O [M+H].sup.+: 316.917116. Found 316.915206.

7-bromo-3-methylnaphthalen-1-ol (32)

[0166] ##STR00053##

[0167] To a solution of 14 (90 mg, 0.28 mmol, 1 equiv.) in dimethylformamide (1.42 mL) was added lithium carbonate (23 mg, 0.31 mmol, 1.1 equiv.). The reaction mixture was stirred at 100? C. for 1.5 hours and then allowed to cool to room temperature. This reaction mixture was treated with ice-cold water and extracted with diethyl ether (3?). The combined extracts were washed a 1M solution of HCl, then with brine, dried over MgSO.sub.4, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel (Toluene/Cyclohexane, 8/2, v/v, UV) to afford 32 as a white solid (49 mg, 73%). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.30 (s, 1H), 7.60-7.49 (m, 2H), 7.17 (s, 1H), 6.65 (s, 1H), 5.24 (s, 1H), 2.42 (s, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 150.4, 136.6, 133.4, 130.0, 128.8, 124.3, 123.9, 119.8, 118.4, 111.8, 21.9. HRMS calculated for CH.sub.10BrO [M+H].sup.+: 236.990953. Found 236.990412. M.p.=105-107? C.

6-bromo-2-methylnaphthalene-1,4-dione (2)

[0168] ##STR00054##

[0169] A solution of 32 (42 mg, 0.18 mmol, 1 equiv.) in a mixture of acetonitrile (2.5 mL) and water (0.9 mL) was prepared. At 0? C., (diacetoxyiodo)benzene (120 mg, 0.37 mmol, 2.1 equiv.) was added portionwise to the stirring solution. The mixture reaction was stirred for 30 minutes at 0? C. then at room temperature for 1 h. A saturated aqueous solution of NaHCO.sub.3 was added to the yellow mixture and it was extracted with ethyl acetate. The organic phases were washed with brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel (Toluene/Cyclohexane, 8/2, v/v, UV) to give a yellow solid (39 mg, 88%). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.16 (d, J=2.0 Hz, 1H), 7.94 (d, J=8.3 Hz, 1H), 7.83 (dd, J=8.3, 2.0 Hz, 1H), 6.83 (q, J=1.5 Hz, 1H), 2.19 (d, J=1.5 Hz, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 184.9, 183.8, 148.6, 136.7, 135.5, 133.4, 130.8, 129.34, 129.29, 128.4, 16.6. HRMS calculated for C.sub.11H.sub.8BrO.sub.2 [M+H].sup.+: 250.970218. Found 250.970402. M.p.=129-130? C.

Example 6: Preparation of 6-chloromenadione

[0170] The 6-chloromenadione is prepared according to the following reaction scheme:

##STR00055##

4-(4-chlorophenyl)-3-methyl-4-oxobut-2-enoic acid (15)

[0171] ##STR00056##

[0172] 15 was synthetized according to Sleebs procedure. A mixture of 1-chloro-4-iodobenzene (10.0 g, 41.94 mmol, 1 equiv.), lithium acetate (6.89 g, 104.37 mmol, 2.49 equiv.), lithium chloride (1.78 g, 41.98 mmol, 1 equiv.), 3-methyl-3-buten-1-ol (4.25 mL, 41.94 mmol, 1 equiv.), tetrabutylammonium chloride hydrate (24.9 g, 83.97 mmol, 2 equiv.) and palladium diacetate (0.53 g, 2.37 mmol, 0.057 equiv.) in dimethylformamide (81 mL) was stirred at 70? C. for 72 h. After this time, the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride. Then, the reaction mixture was extracted three times with diethyl ether. The combined organic layers were washed with brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (Cyclohexane, UV) to afford 15 as an orange oil. .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 9.75-9.71 (m, 1H), 7.30-7.25 (m, 2H), 7.13-7.07 (m, 2H), 2.60 (dd, J=13.5, 6.7 Hz, 1H), 2.51 (dd, J=13.5, 7.1 Hz, 1H), 2.46-2.38 (m, 1H), 2.38-2.31 (m, 1H), 2.27 (ddd, J=15.6, 7.2, 2.2 Hz, 1H), 0.98 (d, J=6.5 Hz, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 202.2, 138.6, 132.0, 130.6 (2C), 128.5 (2C), 50.2, 42.5, 30.1, 19.8.

4-(4-chlorophenyl)-3-methylbutanoic acid (16)

[0173] ##STR00057##

[0174] 200 mL of acetonitrile was added to periodic acid (5.48 g, 24.05 mmol, 1.09 equiv.) and the resulting mixture was stirred for 15 min. At 0? C., a solution of 4-(4-bromophenyl)-3-methylbutanal (4.36 g, 22.17 mmol, 1 equiv.) in acetonitrile (15 mL) was added followed by pyridinium chlorochromate (0.095 g, 0.44 mmol, 0.02 equiv.) in 15 mL of acetonitrile. The reaction mixture was then stirred at room temperature for 4 h. After this time, ethyl acetate was added. The organic phase was washed with a 1:1 water/brine mixture, a saturated aqueous of sodium hydrogen sulfate solution and brine. It was then dried over MgSO.sub.4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (Dichloromethane/methanol, gradient from 98/2 to 95/5, v/v, UV) to afford 16 as a brown oil. .sup.1H NMR (CDCl.sub.3, 500 MHz): ? 7.43-7.39 (m, 2H), 7.27-7.23 (m, 2H), 2.79 (dd, J=13.5, 6.6 Hz, 1H), 2.64 (dd, J=13.5, 7.4 Hz, 1H), 2.50 (dd, J=14.7, 5.5 Hz, 1H), 2.41 (tt, J=12.6, 6.5 Hz, 1H), 2.34 (m, 1H), 1.12 (d, J=6.5 Hz, 3H). .sup.13C NMR (CDCl.sub.3, 126 MHz): ? 179.5, 138.6, 132.1, 130.7 (2C), 128.5 (2C), 42.3, 40.8, 32.1, 19.6. HRMS calculated for C.sub.11H.sub.12ClO.sub.2 [M?H].sup.?: 211.053131. Found 211.052909.

7-chloro-3-methyl-3,4-dihydronaphthalen-1(2H)-one (17)

[0175] ##STR00058##

[0176] Polyphosphoric acid (25 mL) was poured in a 100 mL flask containing 4-(4-bromophenyl)-3-methylbutanoic acid (2.56 g, 12.04 mmol, 1 equiv.). The reaction mixture was stirred slowly overnight at 90? C. After TLC check, the mixture was poured on ice water until PPA was completely dissolved by using sonicator. Then, the aqueous phase was extracted with ethyl acetate (3 times). The reunited organic phases were washed with brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (Toluene/ethyl acetate, gradient from 7/3 to 9/1, v/v, UV) to afford 17 as a brown solid (1.8 g, 77%). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 7.95 (d, J=2.3 Hz, 1H), 7.40 (dd, AB syst, J=8.2, 2.3 Hz, 1H), 7.18 (d, AB syst, J=8.2 Hz, 1H), 2.94 (dd, J=16.2, 3.6 Hz, 1H), 2.72 (dd, J=13.0, 1.8 Hz, 1H), 2.63 (dd, J=16.4, 10.0 Hz, 1H), 2.36-2.24 (m, 2H), 1.13 (d, J=6.2 Hz, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 197.3, 142.1, 133.5, 133.4, 132.9, 130.5, 126.9, 46.9, 37.5, 30.4, 21.4. HRMS calculated for C.sub.11H.sub.12ClO [M+H]+: 195.0571. Found 195.0561. M.p.=49-51? C.

2-bromo-7-chloro-3-methyl-3,4-dihydronaphthalen-1(2H)-one (18)

[0177] ##STR00059##

[0178] A solution of 17 (1.71 g, 8.78 mmol, 1 equiv.) in dichloromethane (3.1 mL) was added dropwise to a solution of N-bromosuccinimide (1.56 g, 8.78 mmol, 1 equiv.) and p-toluenesulfonic acid monohydrate (0.17 g, 0.88 mmol, 0.1 equiv.) in dichloromethane (9.8 mL) at 0? C. The reaction mixture was stirred at reflux for 4 h. After addition of water, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous NaHCO.sub.3 and brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The product 18 was directly engaged in the next step without further purification (94% brut yield).

7-chloro-3-methylnaphthalen-1-ol (19)

[0179] ##STR00060##

[0180] To a solution of 18 (2.25 g, 8.23 mmol, 1 equiv.) in dimethylformamide (41.1 mL) was added lithium carbonate (0.67 g, 9.05 mmol, 1.1 equiv.). The reaction mixture was stirred at 100? C. for 3 h and then allowed to cool to room temperature. This reaction mixture was treated with ice-cold water and extracted with diethyl ether (3?). The combined extracts were washed a 1 M solution of HCl, then with brine, dried over MgSO.sub.4, and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel (Toluene/Cyclohexane, 8/2, v/v, UV) to afford 19 as an orange solid (1.4 g, 88%). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.12 (s, 1H), 7.63 (d, J=8.7 Hz, 1H), 7.42-7.34 (m, 1H), 7.18 (s, 1H), 6.65 (s, 1H), 5.36 (s, 1H), 2.42 (s, 3H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 150.4, 136.3, 133.1, 130.2, 128.6, 127.4, 123.4, 120.9, 119.6, 111.7, 21.7. HRMS calculated for C.sub.11H.sub.9ClO [M]: 192.0336. Found 192.0320. M.p.=105-106? C.

6-chloro-2-methylnaphthalene-1,4-dione (3)

[0181] ##STR00061##

[0182] A solution of 19 (1.32 g, 6.85 mmol, 1 equiv.) in a mixture of acetonitrile (95.1 mL) and water (33.3 mL) was prepared. At 0? C., (diacetoxyiodo)benzene (4.63 g, 14.39 mmol, 2.1 equiv.) was added portionwise to the stirring solution. The mixture reaction was stirred for 30 minutes at 0? C. then at room temperature for 1 h. A saturated aqueous solution of NaHCO.sub.3 was added to the yellow mixture and it was extracted with ethyl acetate. The organic phases were washed with brine, dried over MgSO.sub.4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel (Toluene/Cyclohexane, gradient from 7/3 to 9/1, v/v, UV) to give a yellow solid (860 mg, 61%). .sup.1H NMR (CDCl.sub.3, 400 MHz): ? 8.04 (d, J=8.3 Hz, 1H), 8.01 (d, J=1.9 Hz, 1H), 7.67 (dd, J=8.3, 2.0 Hz, 1H), 6.85 (br d, J=1.0 Hz, 1H), 2.20 (d, J=0.8 Hz, 1H). .sup.13C NMR (CDCl.sub.3, 101 MHz): ? 184.6, 183.8, 148.6, 140.8, 135.6, 133.7, 133.5, 130.4, 128.4, 126.2, 16.6. HRMS calculated for C.sub.11H.sub.3ClO.sub.2 [M+H].sup.+: 207.0207. Found 207.0221. M.p.=115-116? C.