PHOTOREDOX RADICAL BENZYLATION PROCESS

Abstract

The present invention relates to a method for the preparation of a compound having the formula (I):

##STR00001## wherein: R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are in particular H or halogen, R.sup.5 is in particular (C.sub.1-C.sub.6)alkyl, R.sup.6 is a group of formula CH?CH.sub.2 or a group having the below formula (II):

##STR00002## said method comprising a reacting step carried out under light irradiation in the presence of an iron catalyst, a heteroatomic base, and a HAT agent.

Claims

1. A method for preparing a compound of formula (I): ##STR00101## wherein: R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently from each other selected from the group consisting of: H, halogen, OH, (C.sub.1-C.sub.6)alkyl, O(P?O)OAlk.sub.2, Alk being a (C.sub.1-C.sub.6)alkyl group, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, and (C.sub.1-C.sub.6)alkoxy, R.sup.5 is selected from the group consisting of: (C.sub.1-C.sub.6)alkyl, OH, halogen, (C.sub.6-C.sub.10)aryl, (C.sub.6-C.sub.10)aryloxy, (C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl, and OC(?O)(C.sub.1-C.sub.6)alkyl, R.sup.6 is a group of formula CH?CH.sub.2 or a group having the below formula (II): ##STR00102## wherein: n is 0 or an integer varying from 1 to 5; and R, identical or different, is selected from the group consisting of: halo(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl, CN, NO.sub.2, halogen, C(?O)(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkoxy, or two adjacent R groups may form together with the carbon atoms carrying them a (C.sub.6-C.sub.10)aryl group or a heterocycloalkyl group; said method comprising a step of reacting a compound of formula (III): ##STR00103## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 being as defined above in formula (I); with a compound having the following formula (IV):
XCH.sub.2R.sup.6 (IV); wherein R.sup.6 being as defined above in formula (I), and X being a halogen atom; said reacting step being carried out under light irradiation in the presence of an iron catalyst, a heteroatomic base, and a HAT agent.

2. The method of claim 1, wherein the reacting step is carried out at a temperature from 80? C. to 150? C.

3. The method of claim 1, wherein the reacting step is carried out for a time from 12 hours to 72 hours.

4. The method of claim 1, wherein the iron catalyst is a Fe(II) or Fe(III) catalyst.

5. The method of claim 1, wherein the heteroatomic base is selected from the group consisting of: pyridine, picoline, 2,6-lutidine, collidine, and DIPEA.

6. The method of claim 1, wherein the HAT agent is selected from the group consisting of: Hantzsch's esters, analogues thereof, and ?-terpinene.

7. The method of claim 1, wherein the reacting step is carried out in a solvent.

8. The method of claim 1, wherein the reacting step is carried out under blue light irradiation.

9. The method of claim 1, wherein the amount of catalyst is comprised between 2% and 20% in moles in relation to the number of moles of compound of formula (III).

10. The method of claim 1, wherein the amount of heteroatomic base is comprised from 1 to 5 equivalents.

11. The method of claim 1, wherein the amount of HAT agent is comprised from 0.2 to 5 equivalents.

12. The method of claim 1, wherein the amount of compound of formula (IV) is comprised from 1 to 5 equivalents in relation to the amount of compound of formula (III).

13. The method of claim 1, wherein, in formula (I): R.sup.1 is selected from the group consisting of: H, halogen, O(P?O)OAlk.sub.2, Alk being as defined in claim 1, halo(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, and (C.sub.1-C.sub.6)alkoxy; R.sup.2 is selected from the group consisting of: H, OH, and (C.sub.1-C.sub.6)alkoxy; and R.sup.3 and R.sup.4 are H.

14. The method of claim 13, wherein R.sup.1 is H or F, and R.sup.2 is selected from the group consisting of: H, OH, and (C.sub.1-C.sub.6)alkoxy.

15. A compound having the formula (V): ##STR00104## R.sup.7 being selected from the group consisting of: halogen, (C.sub.6-C.sub.10)aryl, (C.sub.6-C.sub.10)aryloxy, and (C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl.

16. The method of claim 1, wherein the iron catalyst is selected from the group consisting of: FeCl.sub.2, FeCl.sub.3, Fe(acac).sub.2, Fe(acac).sub.3, Fe(ClO.sub.4).sub.3, Fe(NO.sub.3).sub.3, and ((NH.sub.4).sub.2Fe(SO.sub.4).sub.2.Math.6H.sub.2O).

17. The method of claim 1, wherein the reacting step is carried out in a solvent, said solvent selected from the group consisting of: acetonitrile, toluene, hexafluoroisopropanol, dichloroethane, dimethylformamide, ethyl acetate, and isopropanol.

18. The method of claim 1, wherein the reacting step is carried out at 90? C.

19. The method of claim 1, wherein the reacting step is carried out for 24 hours.

20. The compound of claim 15, wherein the compound is: ##STR00105##

Description

EXAMPLES

General Information

[0208] Solvents and reagents: Commercially available starting materials were purchased from Sigma-Aldrich, ABCR GmbH & Co. KG, Alfa Aesar, and Apollo Scientific and were used without further purification. Solvents were obtained from Sigma-Aldrich and LPCR. All reactions were performed in standard glassware. Thin Layer Chromatography (TLC) were used to monitor reactions (vide infra). Crude mixtures were purified by flash column chromatography. The latter were performed using silica gel 60 (230-400 mesh, 0.040-0.063 mm) purchased from E. Merck. Automatic flash chromatographies were carried out in a Biotage Puriflash apparatus with UV-Vis detection at 254 nm (unless otherwise specified). Monitoring and primary characterization of products were achieved by Thin Layer Chromatography on aluminum sheets coated with silica gel 60 F254 purchased from E. Merck. Eluted TLC's were revealed under UV (325 nm and 254 nm) and with chemicals. Analytical TLC was carried out on pre-coated Sil G-25 UV.sub.254 plates from Macherey Nagel. Flash chromatography was performed using silica gel G60 (230-400 mesh) from E. Merck. Nuclear.

[0209] Magnetic Resonance (NMR): The Nuclear Magnetic Resonance (NMR) spectra were recorded by a Bruker Avance 400 apparatus (.sup.1H NMR 400 MHz, .sup.13C NMR 100 MHz, .sup.19F NMR 377 MHz) or Bruker Avance III HD500 MHz apparatus (.sup.1H NMR 500 MHz, .sup.13C NMR 125 MHz, .sup.19F NMR.sup.471 MHz) at the ECPM. All chemical shifts (?) are quoted in parts per million (ppm). The chemical shifts are referred to the used partial deuterated NMR solvent (for CDCl.sub.3: .sup.1H NMR, 7.26 ppm and .sup.13C NMR, 77.00 ppm; for MeCN: .sup.1H NMR, 1.93 ppm and .sup.13C NMR 1.3 and 118.2 ppm). The coupling constants (J) and the non equivalence (?v) are given in Hertz (Hz). Resonance patterns are reported with the following notations: br (broad), s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), AB (AB system), (ABX) (AB system of an ABX) and A.sub.2B.sub.2 (A.sub.2B.sub.2 aromatic system). In addition, the following acronyms will be used: C?O carbonyl group; C.sub.q: quaternary carbon; CH.sub.2: secondary carbon; CH.sub.3: methyl group.

[0210] Microanalyses: Microanalyses were obtained at Service de Microanalyses at the Institute de Chimie de Strasbourg.

[0211] Mass spectrometry: Mass spectra (ESI-MS) were obtained on a microTOF LC spectrometer (Bruker Daltonics, Bremen). High Resolution Mass (HRMS) spectra were measured and fitted with calculated data.

[0212] Melting point: Melting points were determined on a Blichi melting point apparatus and were not corrected.

General Procedure for the Photocatalytic Benzylation of Quinones

[0213] In a 10 mL tube, quinone (0.5 mmol), benzyl bromide (0.75 mmol) and Fe(acac).sub.3 (10%) were dissolved in Acetonitrile (5 mL). The mixture was put under agitation and 2,6-lutidine (0.6 mmol) and ?-terpinene (0.6 mmol) were added successively. The tube was sealed, put under blue light irradiation and heated up at 90? C. during 24 h. After completion, the mixture was allowed to cool down at room temperature and was partitioned between ethyl acetate (10 mL) and aqueous 1M HCl (10 mL). The aqueous layer was extracted once with 10 mL ethyl acetate and the reunited organic layers were washed with brine and dried with MgSO.sub.4. The solvent was removed and the crude was purified by silica gel chromatography to obtained pure benzylated quinone.

Example 1: Preparation of 2-methyl-3-(4-(trifluoromethyl)benzoyl) naphthalene-1,4-dione (MD272)

[0214] ##STR00044##

[0215] According to the general procedure, menadione and 4-trifluoromethylbenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=1:1, UV), 139 mg (0.42 mmol, 84% yield) of MD272 were isolated as a yellow solid. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.13-8.02 (m, 2H), 7.74-7.65 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 4.08 (s, 2H), 2.25 (s, 3H). .sup.19F NMR (471 MHz, Chloroform-d) ? ?62.45. .sup.13C NMR (126 MHz, Chloroform-d) ? 185.22, 184.60, 144.99, 144.51, 142.34, 133.78, 133.76, 132.19, 132.01, 129.01, 128.94 (q, J=32.3 Hz), 126.64, 126.51, 125.70 (q, J=3.8 Hz), 124.26 (q, J=271.8 Hz), 32.47, 13.47.

Example 2: Preparation of 4-(3-methyl-1,4-dioxo-1,4-dihydronaphthalene-2-carbonyl)benzonitrile (MD402)

[0216] ##STR00045##

[0217] According to the general procedure, menadione and 4-cyannobenzyl bromide were used. After chromatography on silica gel (Toluene, UV), 108 mg (0.38 mmol, 75% yield) of MD402 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.15-8.01 (m, 2H), 7.82-7.66 (m, 2H), 7.63-7.50 (m, 2H), 7.41-7.30 (m, 2H), 4.08 (s, 2H), 2.24 (s, 3H). .sup.13C NMR (101 MHz, Chloroform-d) ? 185.11, 184.55, 145.22, 144.04, 143.85, 133.91, 133.86, 132.60, 132.18, 131.95, 129.49, 126.68, 126.60, 118.88, 110.62, 32.82, 13.55.

Example 3: Preparation of 2-benzyl-3-methylnaphthalene-1,4-dione (MD404)

[0218] ##STR00046##

[0219] According to the general procedure, menadione and benzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 90 mg (0.34 mmol, 69% yield) of MD404 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.14-8.03 (m, 2H), 7.70 (dd, J=5.7, 3.3 Hz, 2H), 7.44-6.92 (m, 5H), 4.04 (s, 2H), 2.25 (s, 3H). .sup.13C NMR (101 MHz, Chloroform-d) ? 185.53, 184.79, 145.48, 144.57, 138.19, 133.63, 133.60, 132.27, 132.18, 128.79, 128.73, 126.62, 126.56, 126.41, 32.55, 13.41.

Example 4: Preparation of 2-(3,5-dimethylbenzyl)-3-methylnaphthalene-1,4-dione (MD412)

[0220] ##STR00047##

[0221] According to the general procedure, menadione and 3,5-dimethylbenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 101 mg (0.35 mmol, 70% yield) of MD412 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.15-8.00 (m, 2H), 7.70 (dd, J=5.8, 3.3 Hz, 2H), 7.02-6.63 (m, 3H), 3.96 (s, 2H), 2.26 (s, 6H), 2.25 (s, 3H). .sup.13C NMR (101 MHz, Chloroform-d) ? 185.64, 184.85, 145.65, 144.54, 138.31, 138.00, 133.60, 133.56, 132.32, 132.25, 128.26, 126.67, 126.47, 126.39, 32.39, 21.44, 13.45.

Example 5: Preparation of 2-methyl-3-(4-nitrobenzyl)naphthalene-1,4-dione (MD417)

[0222] ##STR00048##

[0223] According to the general procedure, menadione and 4-nitrobenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Ethyl acetate=9:1, UV), 118 mg (0.38 mmol, 77% yield) of MD417 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.09-7.96 (m, 4H), 7.70-7.60 (m, 2H), 7.38-7.28 (m, 2H), 4.06 (s, 2H), 2.19 (s, 3H). .sup.13C NMR (101 MHz, Chloroform-d) ? 185.08, 184.53, 146.83, 145.97, 145.31, 143.96, 133.95, 133.90, 132.18, 131.94, 129.53, 126.71, 126.63, 124.05, 32.64, 13.59.

Example 6: Preparation of 2-(4-fluorobenzyl)-3-methylnaphthalene-1,4-dione (MD420)

[0224] ##STR00049##

[0225] According to the general procedure, menadione and 4-fluorobenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=3:7, UV), 93 mg (0.33 mmol, 66% yield) of MD420 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.15-8.04 (m, 2H), 7.76-7.66 (m, 2H), 7.22-7.16 (m, 2H), 7.00-6.90 (m, 2H), 4.00 (s, 2H), 2.25 (s, 3H). .sup.19F NMR (377 MHz, Chloroform-d) ? ?116.52-?116.64 (m). .sup.13C NMR (126 MHz, Chloroform-d) ? 185.40, 184.72, 161.62 (d, J=244.7 Hz), 145.23, 144.49, 133.81 (d, J=3.3 Hz), 133.66, 132.20, 132.09, 130.17 (d, J=7.8 Hz), 126.59, 126.43, 115.56 (d, J=21.3 Hz), 31.77, 13.37.

Example 7: Preparation of methyl 4-((3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methyl)benzoate (MD422)

[0226] ##STR00050##

[0227] According to the general procedure, menadione and methyl 4-(bromomethyl)benzoate were used. After chromatography on silica gel (Toluene, UV), 80 mg (0.25 mmol, 50% yield) of MD422 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.12-8.06 (m, 2H), 7.95-7.91 (m, 2H), 7.74-7.68 (m, 2H), 7.29 (d, J=8.5 Hz, 2H), 4.08 (s, 2H), 3.88 (s, 3H), 2.23 (s, 3H). .sup.13C NMR (101 MHz, Chloroform-d) ? 185.30, 184.63, 166.98, 145.00, 144.68, 143.61, 133.75, 132.23, 132.06, 130.11, 128.70, 128.57, 126.66, 126.51, 52.18, 32.65, 13.48.

Example 8: Preparation of 2-(3-fluoro-4-nitrobenzyl)-3-methyl-naphthalene-1,4-dione (MD440)

[0228] ##STR00051##

[0229] According to the general procedure, menadione and 4-nitro-3-fluorobenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 91 mg (0.28 mmol, 56% yield) of MD440 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.16-8.05 (m, 2H), 7.99 (dd, J=8.7, 7.7 Hz, 1H), 7.82-7.65 (m, 2H), 7.22-7.11 (m, 2H), 4.10 (s, 2H), 2.26 (s, 3H). .sup.19F NMR (377 MHz, Chloroform-d) ? ?116.59 (m). .sup.13C NMR (101 MHz, Chloroform-d) ? 184.92, 184.41, 155.82 (d, J=265.6 Hz), 147.72 (d, J=8.0 Hz), 145.58, 143.24, 135.94, 134.07, 133.99, 132.16, 131.85, 126.73 (d, J=4.0 Hz), 126.56 (d, J=2.5 Hz), 124.80, 124.76, 118.48 (d, J=21.3 Hz), 32.58 (d, J=1.4 Hz), 13.63.

Example 9: Preparation of 2-(4-iodobenzyl)-3-methylnaphthalene-1,4-dione (MD444)

[0230] ##STR00052##

[0231] According to the general procedure, menadione and 4-iodobenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 158 mg (0.407 mmol, 81% yield) of MD444 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.18-7.99 (m, 2H), 7.79-7.64 (m, 2H), 7.60-7.47 (m, 2H), 7.03-6.86 (m, 2H), 3.97 (s, 2H), 2.24 (s, 3H). .sup.13C NMR (101 MHz, Chloroform-d) ? 185.35, 184.69, 144.86, 144.74, 137.91, 137.84, 133.73, 132.23, 132.08, 130.78, 126.65, 126.50, 91.81, 32.17, 13.46.

Example 10: Preparation of 2-methyl-3-(2-methylbenzyl)naphthalene-1,4-dione (MD454)

[0232] ##STR00053##

[0233] According to the general procedure, menadione and 2-methylbenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 92 mg (0.33 mmol, 67% yield) of MD454 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.15-8.11 (m, 1H), 8.11-8.06 (m, 1H), 7.77-7.67 (m, 2H), 7.20 (dd, J=7.3, 1.6 Hz, 1H), 7.11 (td, J=7.4, 1.5 Hz, 1H), 7.04 (td, J=7.6, 1.6 Hz, 1H), 6.84 (dd, J=7.6, 1.3 Hz, 1H), 3.97 (s, 2H), 2.45 (s, 3H), 2.16 (s, 3H). .sup.13C NMR (101 MHz, Chloroform-d) ? 185.32, 184.58, 145.65, 145.49, 136.39, 136.14, 133.65, 133.61, 132.38, 132.26, 130.47, 126.73, 126.68, 126.51, 126.47, 126.27, 29.70, 20.12, 13.36.

Example 11: Preparation of 2-methyl-3-(4-(trifluoromethoxy)benzyl) naphthalene-1,4-dione (MD456)

[0234] ##STR00054##

[0235] According to the general procedure, menadione and 4-trifluoromethoxybenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 138 mg (0.4 mmol, 80% yield) of MD456 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.12-8.05 (m, 2H), 7.71 (dd, J=5.8, 3.3 Hz, 2H), 7.30-7.22 (m, 2H), 7.11 (dt, J=7.7, 1.0 Hz, 2H), 4.03 (s, 2H), 2.26 (s, 3H). .sup.19F NMR (377 MHz, Chloroform-d) ? ?57.93. .sup.13C NMR (101 MHz, Chloroform-d) ? 185.36, 184.71, 147.93 (q, J=2.0 Hz), 144.90, 144.74, 136.92, 133.75, 132.24, 132.09, 130.04, 129.18, 128.37, 126.65, 126.51, 120.59 (d, J=256.9 Hz), 31.96, 13.46.

Example 12: Preparation of 2-(2,5-dimethoxybenzyl)-3-methyl-naphthalene-1,4-dione (MD463)

[0236] ##STR00055##

[0237] According to the general procedure, menadione and 2,5-dimethoxybenzyl bromide were used. After chromatography on silica gel (Toluene, UV), 128 mg (0.39 mmol, 78% yield) of MD463 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.14-8.01 (m, 2H), 7.80-7.61 (m, 2H), 6.78 (d, J=8.8 Hz, 1H), 6.69 (dd, J=8.8, 3.1 Hz, 1H), 6.62 (d, J=3.0 Hz, 1H), 4.00 (s, 2H), 3.80 (s, 3H), 3.69 (s, 3H), 2.17 (s, 3H). .sup.13C NMR (101 MHz, Chloroform-d) ? 185.54, 184.73, 153.68, 151.67, 145.57, 145.13, 133.54, 133.47, 132.38, 132.37, 127.78, 126.61, 126.38, 116.36, 111.28, 111.05, 56.10, 55.78, 26.85, 13.18.

Example 13: Preparation of 2-methyl-3-(naphthalen-2-ylmethyl) naphthalene-1,4-dione (MD471)

[0238] ##STR00056##

[0239] According to the general procedure, menadione and 2-(bromomethyl)naphthalene were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 107 mg (0.34 mmol, 69% yield) of MD420 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.20-8.04 (m, 2H), 7.85-7.67 (m, 5H), 7.64-7.60 (m, 1H), 7.51-7.34 (m, 3H), 4.21 (s, 2H), 2.29 (s, 3H). .sup.13C NMR (101 MHz, Chloroform-d) ? 185.55, 184.85, 145.37, 144.81, 135.68, 133.68, 133.65, 132.32, 132.30, 132.22, 128.48, 127.74, 127.68, 127.27, 126.93, 126.69, 126.46, 126.26, 125.70, 32.72, 13.50.

Example 14: Preparation of 2-(2-chloro-5-nitrobenzyl)-3-methyl-naphthalene-1,4-dione (MD490)

[0240] ##STR00057##

[0241] According to the general procedure, menadione and 2-chloro-5-nitrobenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 119 mg (0.35 mmol, 70% yield) of MD490 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.15-8.12 (m, 1H), 8.10-8.05 (m, 1H), 8.03 (dd, J=8.8, 2.7 Hz, 1H), 7.85 (d, J=2.7 Hz, 1H), 7.79-7.68 (m, 2H), 7.57 (d, J=8.7 Hz, 1H), 4.17 (s, 2H), 2.19 (s, 3H). .sup.13C NMR (101 MHz, Chloroform-d) ? 184.78, 184.32, 146.87, 146.61, 142.79, 141.06, 137.96, 134.01, 133.95, 132.24, 131.92, 130.58, 126.77, 126.72, 123.97, 122.87, 30.49, 13.61.

Example 15: Preparation of 2-(4-bromo-2-fluorobenzyl)-3-methyl-naphthalene-1,4-dione (MD497)

[0242] ##STR00058##

[0243] According to the general procedure, menadione and 4-bromo-2-fluorobenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 129 mg (0.36 mmol, 72% yield) of MD497 were isolated as a yellow solid. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.13-8.00 (m, 2H), 7.81-7.58 (m, 2H), 7.21 (dd, J=9.6, 2.0 Hz, 1H), 7.16 (dd, J=8.3, 2.0 Hz, 1H), 7.06 (t, J=8.1 Hz, 1H), 3.98 (s, 2H), 2.21 (s, 3H). .sup.19F NMR (471 MHz, Chloroform-d) ? ?113.57 (t, J=8.7 Hz). .sup.13C NMR (126 MHz, Chloroform-d) ? 185.19, 184.55, 160.70 (d, J=250.3 Hz), 145.45, 143.75, 133.75, 132.22, 132.07, 131.74 (d, J=4.9 Hz), 127.65 (d, J=3.6 Hz), 126.64, 126.54, 124.31 (d, J=15.7 Hz), 120.53 (d, J=9.6 Hz), 119.17 (d, J=25.6 Hz), 25.52 (d, J=3.1 Hz), 13.21 (d, J=2.7 Hz).

Example 16: Preparation of 2-(2,5-dibromobenzyl)-3-methylnaphthalene-1,4-dione (MD498)

[0244] ##STR00059##

[0245] According to the general procedure, menadione and 2,5-dibromobenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 156 mg (0.37 mmol, 74% yield) of MD490 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.22-8.02 (m, 2H), 7.83-7.67 (m, 2H), 7.45 (d, J=8.5 Hz, 1H), 7.20 (dd, J=8.5, 2.4 Hz, 1H), 7.00 (d, J=2.3 Hz, 1H), 4.09 (s, 2H), 2.14 (s, 3H). .sup.13C NMR (101 MHz, Chloroform-d) ? 185.04, 184.37, 146.38, 143.84, 139.75, 134.36, 133.87, 132.31, 132.06, 131.56, 131.26, 126.82, 126.64, 123.48, 121.75, 32.81, 13.57.

Example 17: Preparation of 2-methyl-3-(4-methylbenzyl)naphthalene-1,4-dione (MD510)

[0246] ##STR00060##

[0247] According to the general procedure, menadione and 4-methylbenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 71 mg (0.26 mmol, 51% yield) of MD510 were isolated as a yellow solid. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.08 (m, 2H), 7.69 (m, 2H), 7.13 (d, J=8.2 Hz, 2H), 7.07 (d, J=8.1 Hz, 2H), 4.00 (s, 2H), 2.29 (s, 3H), 2.25 (s, 3H). .sup.13C NMR (126 MHz, Chloroform-d) ? 185.59, 184.83, 145.68, 144.36, 136.13, 135.09, 133.59, 133.55, 132.26, 132.21, 129.47, 128.62, 126.60, 126.38, 32.14, 21.12, 13.39.

Example 18: Preparation of 2-(4-chlorobenzyl)-3-methylnaphthalene-1,4-dione (MD522)

[0248] ##STR00061##

[0249] According to the general procedure, menadione and 4-chlorobenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 109 mg (0.37 mmol, 73% yield) of MD522 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.28-7.95 (m, 2H), 7.70 (m, 2H), 7.25-7.20 (m, 2H), 7.19-7.13 (m, 2H), 3.99 (s, 1H), 2.24 (s, 1H). .sup.13C NMR (101 MHz, Chloroform-d) ? 185.36, 184.69, 144.97, 144.68, 136.66, 133.72, 132.41, 132.22, 132.08, 130.07, 128.89, 126.63, 126.48, 31.98, 13.43.

Example 19: Preparation of 2-(4-bromobenzyl)-3-methylnaphthalene-1,4-dione (MD523)

[0250] ##STR00062##

[0251] According to the general procedure, menadione and 4-bromobenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 137 mg (0.402 mmol, 80% yield) of MD523 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.19-8.01 (m, 2H), 7.70 (m, 2H), 7.44-7.35 (m, 2H), 7.16-7.04 (m, 2H), 3.97 (s, 2H), 2.24 (s, 3H). .sup.13C NMR (101 MHz, Chloroform-d) ? 185.34, 184.68, 144.88, 144.71, 10 137.20, 133.72, 132.21, 132.07, 131.85, 130.45, 126.63, 126.48, 120.44, 32.05, 13.44.

Example 20: Preparation of 2-methyl-3-(3-(trifluoromethyl) benzyl)naphthalene-1,4-dione (MD525)

[0252] ##STR00063##

[0253] According to the general procedure, menadione and 3-trifluoromethylbenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 126 mg (0.38 mmol, 76% yield) of MD525 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.09 (m, 2H), 7.71 (m, 2H), 7.53-7.34 (m, 4H), 4.08 (s, 2H), 2.25 (s, 3H). .sup.19F NMR (377 MHz, Chloroform-d) ? ?62.58. .sup.13C NMR (101 MHz, Chloroform-d) ? 185.13, 184.48, 144.86, 144.37, 139.05, 133.64, 132.09, 131.94, 131.92, 131.91, 130.97 (q, J=32.2 Hz), 129.11, 126.55, 126.39, 125.32 (q, J=3.9 Hz), 124.04 (q, J=272.4 Hz), 123.40 (q, J=3.8 Hz), 32.29, 13.35.

Example 21: Preparation of 2-(2,6-dichlorobenzyl)-3-methylnaphthalene-1,4-dione (MD526)

[0254] ##STR00064##

[0255] According to the general procedure, menadione and 2,6-dichlorobenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 126 mg (0.38 mmol, 76% yield) of MD526 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.21-7.99 (m, 2H), 7.75-7.63 (m, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.15-7.08 (m, 1H), 4.37 (s, 2H), 2.04 (s, 3H). 13C NMR (101 MHz, Chloroform-d) ? 185.12, 184.12, 144.58, 144.47, 135.92, 135.46, 133.63, 133.53, 132.24, 132.20, 128.58, 128.30, 126.77, 126.43, 29.48, 12.85.

Example 22: Preparation of 2-methyl-3-(2-(trifluoromethyl)benzyl)naphthalene-1,4-dione (MD529)

[0256] ##STR00065##

[0257] According to the general procedure, menadione and 2-trifluoromethylbenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 126 mg (0.38 mmol, 76% yield) of MD529 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.28-8.01 (m, 2H), 7.78-7.72 (m, 2H), 7.70 (d, J=7.3 Hz, 1H), 7.36 (t, J=7.1 Hz, 1H), 7.30 (t, J=7.3 Hz, 1H), 6.96 (d, J=7.6 Hz, 1H), 4.25 (s, 2H), 2.11 (s, 3H). .sup.19F NMR (377 MHz, Chloroform-d) ? ?60.90. .sup.13C NMR (101 MHz, Chloroform-d) ? 185.13, 184.50, 146.42, 144.36, 136.75, 133.83, 133.81, 132.36, 132.23, 132.10, 128.69 (q, J=29.9 Hz), 128.29, 126.77, 126.60, 126.56, 126.44 (q, J=5.8 Hz), 124.70 (q, J=273.8 Hz), 28.79 (q, J=2.6 Hz), 13.23.

Example 23: Preparation of 2-(3,5-dimethoxybenzyl)-3-methyl-naphthalene-1,4-dione (MD539)

[0258] ##STR00066##

[0259] According to the general procedure, menadione and 3,5-dimethoxybenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Ethyl Acetate=95:5, UV), 110 mg (0.34 mmol, 68% yield) of MD539 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.17-7.99 (m, 2H), 7.74-7.65 (m, 2H), 6.37 (d, J=2.2 Hz, 2H), 6.29 (t, J=2.2 Hz, 1H), 3.97 (s, 2H), 3.75 (s, 6H), 2.24 (s, 3H). .sup.13C NMR (101 MHz, Chloroform-d) ? 185.46, 184.72, 161.04, 145.09, 144.78, 140.42, 133.61, 133.59, 132.27, 132.17, 126.63, 126.40, 106.97, 98.14, 55.39, 32.64, 13.42.

Example 24: Preparation of 2-(2-bromobenzyl)-3-methylnaphthalene-1,4-dione (MD547)

[0260] ##STR00067##

[0261] According to the general procedure, menadione and 2-bromobenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 134 mg (0.39 mmol, 79% yield) of MD547 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.19-7.99 (m, 2H), 7.79-7.64 (m, 2H), 7.59 (dd, J=8.0, 1.4 Hz, 1H), 7.15 (td, J=7.5, 1.4 Hz, 1H), 7.06 (td, J=7.6, 1.8 Hz, 1H), 6.92 (dd, J=7.6, 1.8 Hz, 1H), 4.13 (s, 2H), 2.13 (s, 3H). .sup.13C NMR (101 MHz, Chloroform-d) ? 185.20, 184.51, 146.04, 144.73, 137.49, 133.75, 133.72, 133.05, 132.32, 132.15, 128.77, 128.12, 127.73, 126.72, 126.52, 124.84, 32.83, 13.45.

Example 25: Preparation of 2-(3,5-diiodobenzyl)-3-methylnaphthalene-1,4-dione (TP1)

[0262] ##STR00068##

[0263] According to the general procedure, menadione and 3,5-diiodobenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=1:1, UV), 191 mg (0.37 mmol, 74% yield) of TP1 were isolated as a yellow solid. .sup.1H (400 MHz, Chloroform-d) ? 8.12 (m, 2H), 7.88 (t, J=1.8 Hz, 1H), 7.72 (m, 2H), 7.53-7.50 (m, 2H), 3.91 (s, 2H), 2.23 (s, 3H). .sup.13C NMR (126 MHz, Chloroform-d) ? 185.17, 184.45, 145.21, 143.90, 143.50, 142.27, 136.92, 133.86, 133.83, 132.22, 131.98, 126.76, 126.59, 95.20, 31.73, 13.61.

Example 26: Preparation of 2-(3,5-dibromobenzyl)-3-methylnaphthalene-1,4-dione (TP2)

[0264] ##STR00069##

[0265] According to the general procedure, menadione and 3,5-dibromobenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=1:1, UV), 135 mg (0.32 mmol, 64% yield) of TP2 were isolated as a yellow solid. .sup.1H (400 MHz, Chloroform-d) ? 8.11 (m, 2H), 7.75-7.71 (m, 2H), 7.51 (t, J=1.8 Hz, 1H), 7.30 (m, 2H), 3.91 (s, 2H), 2.23 (s, 3H). .sup.13C NMR (126 MHz, Chloroform-d) ? 185.17, 184.47, 145.27, 143.88, 142.07, 133.88, 133.86, 132.45, 132.22, 131.98, 130.49, 126.77, 126.61, 123.25, 32.00, 13.59.

Example 27: Preparation of 2-(3-fluoro-4-(trifluoromethyl)benzyl)-3-methyl naphthalene-1,4-dione (MD565)

[0266] ##STR00070##

[0267] According to the general procedure, menadione and 3-fluro-4-trifluoromethylbenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 129 mg (0.37 mmol, 74% yield) of MD565 were isolated as a yellow solid. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.16-8.00 (m, 2H), 7.81-7.66 (m, 2H), 7.50 (t, J=7.7 Hz, 1H), 7.12 (dd, J=8.1, 1.2 Hz, 1H), 7.09-7.02 (m, 1H), 4.07 (s, 2H), 2.25 (s, 3H). .sup.19F NMR (471 MHz, Chloroform-d) ? ?61.20 (d, J=12.2 Hz), -114.07 (td, J=12.0, 7.3 Hz). .sup.13C NMR (126 MHz, Chloroform-d) ? 185.08, 184.50, 159.97 (dq, J=256.4, 2.1 Hz), 145.36, 145.30, 143.80, 133.93, 133.88, 132.19, 131.94, 127.45 (qd, J=4.4, 2.1 Hz), 126.71, 126.61, 124.32 (d, J=3.5 Hz), 122.71 (q, J=272.0 Hz), 117.05 (d, J=21.0 Hz), 116.72 (qd, J=33.2, 12.3 Hz), 32.36, 13.53.

Example 28: Preparation of 2-methyl-3-((perfluorophenyl) methyl)naphthalene-1,4-dione (MD566)

[0268] ##STR00071##

[0269] According to the general procedure, menadione and 2,3,4,5,6-pentafluorobenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 125 mg (0.35 mmol, 71% yield) of MD566 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.09-8.04 (m, 1H), 8.03-7.98 (m, 1H), 7.75-7.63 (m, 2H), 4.03 (s, 2H), 2.24 (s, 3H). .sup.19F NMR (471 MHz, Chloroform-d) ? ?141.23-?141.33 (m), ?156.45 (t, J=20.9 Hz), ?162.22-?162.38 (m). .sup.13C NMR (126 MHz, Chloroform-d) ? 184.78, 183.76, 145.54, 145.41 (dm, J=247.0 Hz), 141.96, 140.15 (dm, J=252.7 Hz), 138.81-136.39 (dm, J=251.8 Hz), 133.83, 133.80, 132.08, 131.85, 126.57, 126.56, 112.13 (td, J=17.5, 4.1 Hz), 21.01, 13.04.

Example 29: Preparation of 2-allyl-3-methylnaphthalene-1,4-dione (MD598)

[0270] ##STR00072##

[0271] A variant from the general procedure was performed. In a 10 mL tube, quinone (0.5 mmol), allyl bromide (1 mmol) and Fe(acac).sub.3 (10%) were dissolved in Acetonitrile (5 mL). The mixture was put under agitation and 2,6-lutidine (0.6 mmol) and ?-terpinene (0.6 mmol) were added successively. The tube was sealed, put under blue light irradiation and heated up at 90? C. during 24 h. After completion, the mixture was allowed to cool down at room temperature and was partitioned between ethyl acetate (10 mL) and aqueous 1M HCl (10 mL). The aqueous layer was extracted once with 10 mL ethyl acetate and the reunited organic layers were washed with brine and dried with MgSO.sub.4. The solvent was removed and the crude was purified by silica gel chromatography (Cyclohexane:Ethyl Acetate=95:5, UV) to obtained 72 mg (0.34 mmol, 68%) of MD598 as an orange solid. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.11-8.03 (m, 2H), 7.75-7.60 (m, 2H), 5.83 (ddt, J=17.1, 10.1, 6.3 Hz, 1H), 5.15-5.01 (m, 2H), 3.41 (dd, J=6.3, 0.7 Hz, 2H), 2.19 (s, 3H). .sup.13C NMR (126 MHz, Chloroform-d) ? 185.37, 184.38, 144.41, 144.40, 133.57, 133.53, 133.32, 132.27, 132.20, 126.50, 126.40, 116.76, 31.05, 12.73.

Example 30: Preparation of 2-bromo-3-(4-(trifluoromethyl) benzyl)naphthalene-1,4-dione (MD537) (Compound 1)

[0272] ##STR00073##

[0273] According to the general procedure, 2-bromonaphthalene-1,4-dione and 4-trifluoromethylbenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 84 mg (0.21 mmol, 43% yield) of MD537 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 8.19-8.15 (m, 1H), 8.14-8.08 (m, 1H), 7.85-7.70 (m, 2H), 7.59-7.48 (m, 4H), 4.29 (s, 2H). .sup.19F NMR (377 MHz, Chloroform-d) ? ?62.56. .sup.13C NMR (101 MHz, Chloroform-d) ? 181.82, 177.83, 149.18, 140.75, 140.54, 134.54, 134.34, 131.50, 131.23, 129.61, 129.05 (q, J=36.5 Hz), 127.81, 127.47, 125.72 (q, J=3.8 Hz), 124.24 (q, J=272.0 Hz), 36.91.

Example 31: Preparation of 5-hydroxy-2-methyl-3-(4-(trifluoromethyl) benzyl)naphthalene-1,4-dione (MD536)

[0274] ##STR00074##

[0275] According to the general procedure, Plumbagin and 4-trifluoromethylbenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 64 mg (0.185 mmol, 37% yield) of MD536 were isolated as an orange solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 12.06 (s, 1H), 7.67-7.55 (m, 2H), 7.54 (d, J=8.2 Hz, 2H), 7.35 (d, J=7.9 Hz, 2H), 7.24 (dd, J=8.2, 1.4 Hz, 1H), 4.07 (s, 2H), 2.25 (s, 3H). .sup.19F NMR (471 MHz, CDCl.sub.3) ? ?62.46. .sup.13C NMR (126 MHz, CDCl.sub.3) ? 189.70, 184.40, 161.47, 146.41, 144.30, 141.99, 136.35, 132.15, 129.10 (q, J=32.4 Hz), 128.94, 125.78 (q, J=3.8 Hz), 124.23, 124.22 (q, J=272.1 Hz), 119.26, 114.92, 31.85, 13.59.

Example 32: Preparation of 5-methoxy-2-methyl-3-(4-(trifluoromethyl)benzyl)naphthalene-1,4-dione (MD546)

[0276] ##STR00075##

[0277] According to the general procedure, 5-methoxy-2-methylnaphthalene-1,4-dione and 4-trifluoromethylbenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 90 mg (0.25 mmol, 50% yield) of MD546 were isolated as an orange solid. .sup.1H NMR (400 MHz, Chloroform-d) ? 7.76 (dd, J=7.6, 1.1 Hz, 1H), 7.64 (dd, J=8.5, 7.7 Hz, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.35 (d, J=7.9 Hz, 2H), 7.27 (d, J=8.5 Hz, 1H), 4.05 (s, 2H), 3.99 (s, 3H), 2.19 (s, 3H). .sup.19F NMR (377 MHz, Chloroform-d) ? ?62.45. .sup.13C NMR (101 MHz, Chloroform-d) ? 185.52, 183.83, 159.72, 146.18, 142.65, 142.61, 134.86, 134.44, 129.07, 128.80 (q, J=32.5 Hz), 125.63 (q, J=3.6 Hz), 124.26 (q, J=271.8 Hz), 119.84, 119.30, 117.69, 56.59, 32.67, 13.20.

Example 33: Preparation of 2-chloro-3-(4-(trifluoromethyl) benzyl)naphthalene-1,4-dione (MD587) (Compound 2)

[0278] ##STR00076##

[0279] According to the general procedure, 2-chloronaphthalene-1,4-dione and 4-trifluoromethyl-benzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 95 mg (0.27 mmol, 54% yield) of MD587 were isolated as a yellow solid. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.19-8.15 (m, 1H), 8.11 (m, 1H), 7.81-7.72 (m, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 4.23 (s, 3H). .sup.19F NMR (471 MHz, Chloroform-d) ?62.54. ? .sup.13C NMR (126 MHz, Chloroform-d) ? 182.41, 177.83, 145.66, 144.37, 140.89, 134.59, 134.36, 131.63, 131.43, 129.66, 129.39 (q, J=32.6 Hz), 127.47, 127.37, 125.75 (q, J=3.7 Hz), 124.23 (q, J=272.3 Hz), 33.91.

Example 34: Preparation of 6-fluoro-2-methyl-3-(4-(trifluoromethyl)benzyl) naphthalene-1,4-dione (MD593)

[0280] ##STR00077##

[0281] According to the general procedure, 6-fluoro-2-methylnaphthalene-1,4-dione and 4-trifluoromethyl-benzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=1:1, UV), 116 mg (0.33 mmol, 67% yield) of MD593 were isolated as a yellow solid. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.13 (dd, J=8.6, 5.2 Hz, 1H), 7.72 (dd, J=8.5, 2.7 Hz, 1H), 7.55-7.48 (m, 2H), 7.40-7.30 (m, 3H), 4.08 (s, 2H), 2.26 (s, 3H). .sup.19F NMR (471 MHz, Chloroform-d) ? ?62.49, ?102.18 (td, J=8.4, 5.3 Hz). .sup.13C NMR (126 MHz, Chloroform-d) ? 183.82, 183.45, 166.05 (d, J=257.1 Hz), 145.18, 144.58 (d, J=1.8 Hz), 141.98, 134.48 (d, J=7.8 Hz), 129.73 (d, J=8.9 Hz), 128.97 (q, J=32.3 Hz), 128.90, 128.69 (d, J=3.3 Hz), 125.66 (q, J=3.8 Hz), 124.13 (q, J=271.9 Hz), 120.90 (d, J=22.5 Hz), 113.26 (d, J=23.5 Hz), 32.41, 13.41.

Example 35: Preparation of 2-ethyl-3-(4-(trifluoromethyl)benzyl) naphthalene-1,4-dione (MD602)

[0282] ##STR00078##

[0283] According to the general procedure, 2-ethylnaphthalene-1,4-dione and 4-trifluoromethylbenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=1:1, UV), 108 mg (0.31 mmol, 63% yield) of MD602 were isolated as an orange solid. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.15-7.99 (m, 2H), 7.78-7.65 (m, 2H), 7.52 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 4.09 (s, 2H), 2.72 (q, J=7.6 Hz, 2H), 1.09 (t, J=7.5 Hz, 3H). .sup.19F NMR (471 MHz, Chloroform-d) ? ?62.44. .sup.13C NMR (126 MHz, Chloroform-d) ? 185.12, 184.90, 150.21, 143.78, 142.81, 133.80, 133.75, 132.35, 132.05, 128.93 (q, J=32.4 Hz), 128.89, 126.59, 126.50, 125.69 (q, J=3.7 Hz), 124.29 (q, J=271.9 Hz), 32.08, 21.08, 13.61.

Example 36: Preparation of 2-phenyl-3-(4-(trifluoromethyl)benzyl) naphthalene-1,4-dione (MD603) (Compound 3)

[0284] ##STR00079##

According to the general procedure, 2-phenylnaphthalene-1,4-dione and 4-trifluoromethyl-benzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=1:1, UV), 175 mg (0.45 mmol, 89% yield) of MD603 were isolated as an orange solid. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.22-8.04 (m, 2H), 7.76 (m, 2H), 7.55-7.39 (m, 5H), 7.25-7.16 (m, 2H), 7.14-7.06 (m, 2H), 3.97 (s, 2H). .sup.19F NMR (471 MHz, Chloroform-d) ? ?62.44. .sup.13C NMR (126 MHz, Chloroform-d) ? 185.32, 184.63, 147.74, 145.05, 142.76, 134.13, 133.98, 133.22, 132.14, 129.22, 129.13, 129.04, 128.79 (q, J=32.4 Hz), 128.55, 126.85, 126.67, 125.46 (q, J=3.8 Hz), 124.29 (q, J=271.8 Hz), 33.40.

Example 37: Preparation of 1,4-dioxo-3-(4-(trifluoromethyl)benzyl)-1,4-dihydronaphthalen-2-yl acetate (MD611)

[0285] ##STR00080##

[0286] According to the general procedure, 1,4-dioxo-1,4-dihydronaphthalen-2-yl acetate and 4-trifluoromethylbenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=1:9, UV), 91 mg (0.24 mmol, 49% yield) of MD611 were isolated as an orange solid. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.16-8.04 (m, 2H), 7.77-7.70 (m, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 3.97 (s, 2H), 2.41 (s, 3H). .sup.19F NMR (471 MHz, Chloroform-d) ? ?62.49. .sup.13C NMR (126 MHz, Chloroform-d) ? 184.23, 178.17, 167.91, 151.94, 141.44, 136.75, 134.47, 134.22, 131.91, 130.93, 129.41, 129.20 (q, J=32.4 Hz), 127.01, 126.88, 125.71 (q, J=3.8 Hz), 124.23 (q, J=272.0 Hz), 30.12, 20.52.

Example 38: Preparation of 2-phenoxy-3-(4-(trifluoromethyl)benzyl) naphthalene-1,4-dione (MD607) (Compound 4)

[0287] ##STR00081##

[0288] According to the general procedure, 2-phenoxynaphthalene-1,4-dione and 4-trifluoromethyl-benzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=1:1, UV), 85 mg (0.21 mmol, 42% yield) of MD607 were isolated as a yellow solid. .sup.1H NMR (500 MHz, Chloroform-d) ? 8.22-8.11 (m, 1H), 8.02-7.94 (m, 1H), 7.75 (td, J=7.5, 1.5 Hz, 1H), 7.71 (td, J=7.5, 1.5 Hz, 1H), 7.52-7.43 (m, 4H), 7.35-7.29 (m, 2H), 7.15-7.08 (m, 1H), 6.94-6.88 (m, 2H), 4.08 (s, 2H). .sup.19F NMR (471 MHz, Chloroform-d) ? ?62.44. .sup.13C NMR (126 MHz, Chloroform-d) ? 184.89, 179.76, 157.14, 153.96, 142.20, 136.68, 134.39, 134.05, 131.97, 131.31, 129.90, 129.85, 128.99 (q, J=32.4 Hz), 126.83, 126.77, 125.57 (q, J=3.8 Hz), 124.30 (q, J=272.0 Hz), 123.70, 116.36, 29.77.

Example 39: Preparation of 2-benzyl-3-(4-(trifluoromethyl)benzyl) naphthalene-1,4-dione (MD614) (Compound 5)

[0289] ##STR00082##

[0290] According to the general procedure, 2-benzylnaphthalene-1,4-dione and 4-trifluoromethyl-benzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=4:6, UV), 113 mg (0.28 mmol, 56% yield) of MD614 were isolated as a yellow solid. .sup.1H NMR (500 MHz, Chloroform-d) 8.17-8.01 (m, 2H), 7.83-7.66 (m, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.27-7.12 (m, 7H), 4.13 (s, 2H), 4.10 (s, 2H). .sup.19F NMR (471 MHz, Chloroform-d) ? ?62.45. .sup.13C NMR (126 MHz, Chloroform-d) ? 185.15, 185.09, 146.78, 145.46, 142.18, 137.80, 133.97, 133.93, 132.13, 132.06, 128.97, 128.96 (q, J=32.6 Hz), 128.90, 128.60, 126.78, 126.67, 125.66 (q, J=3.9 Hz), 124.26 (q, J=272.1 Hz), 32.63, 32.61.

Example 40: Preparation of 2-(3-fluorobenzyl)-3-methylnaphthalene-1,4-dione (MRO0039)

[0291] ##STR00083##

[0292] According to the general procedure, 2-benzylnaphthalene-1,4-dione and 3-fluorobenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=1:4, UV), 84 mg (0.30 mmol, 60% yield) of MRO0039 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.96 (dd, J=5.7, 3.3 Hz, 2H), 7.57 (dd, J=5.8, 3.3 Hz, 2H), 7.15-7.07 (m, 1H), 6.92-6.87 (m, 1H), 6.83-6.72 (m, 2H), 3.90 (s, 2H), 2.12 (s, 3H). .sup.19F NMR (377 MHz, Chloroform-d) ? ?112.88 (ddd, J=9.9, 8.7, 6.0 Hz). .sup.13C NMR (101 MHz, Chloroform-d) ? 185.3, 184.6, 163.0 (d, J=247.5 Hz), 144.8, 144.7, 140.6 (d, J=8.1 Hz), 133.7 (2C), 132.2, 132.0, 130.1 (d, J=9.1 Hz), 136.6, 126.4, 124.3 (d, J=3.0 Hz), 115.6 (d, J=21.2 Hz), 113.5 (d, J=21.2 Hz), 32.2 (d, J=2.0 Hz), 13.4.

Example 41: Preparation of 2-(3-cyanobenzyl)-3-methylnaphthalene-1,4-dione (MRO0041)

[0293] ##STR00084##

[0294] According to the general procedure, 2-benzylnaphthalene-1,4-dione and 3-cyanobenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=1:4, UV), 95 mg (0.33 mmol, 66% yield) of MRO0041 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) 8.09-8.01 (m, 2H), 7.72-7.66 (m, 2H), 7.52 7.45 (m, 3H), 7.36 (t, J=7.7 Hz, 1H), 4.03 (s, 2H), 2.23 (s, 3H). .sup.13C NMR (101 MHz, Chloroform-d) ? 185.0, 184.4, 145.0, 143.9, 139.7, 133.8, 133.7, 133.2, 132.10, 132.07, 131.8, 130.3, 129.5, 126.6, 126.5, 118.7, 112.8, 32.1, 13.4.

Example 42: Preparation of 3-benzyl-6-fluoro-2-methylnaphthalene-1,4-dione (MRO0010)

[0295] ##STR00085##

According to the general procedure, 6-fluoro-2-methylnaphthalene-1,4-dione and benzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=3:7, UV), 94 mg (0.34 mmol, 67% yield) of MRO0010 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) 8.12 (dd, J=8.6, 5.3 Hz, 1H), 7.72 (dd, J=8.6, 2.7 Hz, 1H), 7.35 (td, J=8.3, 2.7 Hz, 1H), 7.30-7.16 (m, 5H), 4.02 (s, 2H), 2.25 (s, 3H). .sup.19F NMR (377 MHz, Chloroform-d) ? ?102.57 (td, J=8.6, 5.3 Hz). .sup.13C NMR (101 MHz, Chloroform-d) ? 184.2, 183.6 (d, J=1.0 Hz), 166.1 (d, J=263.0 Hz), 145.6 (d, J=2.0 Hz), 144.8, 137.9, 134.7 (d, J=11.1 Hz), 129.7 (d, J=9.1 Hz), 128.9, 128.8 (2C), 128.7 (2C), 126.7, 120.7 (d, J=22.2 Hz), 113.3 (d, J=23.2 Hz), 32.6, 13.4.

Example 43: 3-((7-fluoro-3-methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methyl)benzonitrile (MRO0042)

[0296] ##STR00086##

[0297] According to the general procedure, 6-fluoro-2-methylnaphthalene-1,4-dione and 3-cyanobenzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=1:4, UV), 65 mg (0.34 mmol, 43% yield) of MRO0042 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) 8.12 (dd, J=8.6, 5.2 Hz, 1H), 7.69 (dd, J=8.5, 2.6 Hz, 1H), 7.51-7.45 (m, 3H), 7.41-7.33 (m, 2H), 4.04 (s, 2H), 2.24 (s, 3H). .sup.19F NMR (377 MHz, Chloroform-d) ? ?102.04 (td, J=8.3, 5.3 Hz). .sup.13C NMR (101 MHz, Chloroform-d) ? 183.7, 183.4 (d, J=1.0 Hz), 166.1 (d, J=258.6 Hz), 145.4, 144.1 (d, J=2.0 Hz), 139.5, 134.4 (d, J=8.1 Hz), 133.2, 132.1, 130.5, 129.8 (d, J=9.1 Hz), 129.6, 128.7 (d, J=4.0 Hz), 121.1 (d, J=22.2 Hz), 118.7, 113.3 (d, J=24.2 Hz), 112.9, 32.2, 13.5.

[0298] The process of the invention was also carried out with other reaction conditions, as shown hereafter.

##STR00087##

Procedure:

[0299] In a 10 mL tube, quinone (0.5 mmol), benzyl bromide (0.75 mmol) and iron catalyst were dissolved in the solvent (5 mL). The mixture was put under agitation and base and HAT agent were added successively. The tube was sealed, put under blue light irradiation and heated up at 90? C. during 24 h. After completion, the mixture was allowed to cool down at room temperature and was partitioned between ethyl acetate (10 mL) and aqueous 1M HCl (10 mL). The aqueous layer was extracted once with 10 mL ethyl acetate and the reunited organic layers were washed with brine and dried with MgSO.sub.4. The solvent was removed and the crude was purified by silica gel chromatography to obtained pure benzylated quinone.

TABLE-US-00001 Temperature Cat Base Reductant Duration Yield 3a Solvent (? C.) (mol %) (Equiv) (Equiv) (h) (%) MeCN 90? C. Fe(acac).sub.3 2,6-lutidine ?-terpinene 24 h 84% (10%) (1.2) (1.2) MeCN 90? C. Fe(acac).sub.3 collidine ?-terpinene 24 h 73% (10%) (1.2) (1.2) MeCN 90? C. Fe(acac).sub.3 DIPEA ?-terpinene 24 h 31% (10%) (1.2) (1.2) MeCN 90? C. Fe(acac).sub.3 2,6-lutidine Hantschz ester 24 h 72% (10%) (1.2) (1.2) MeCN 90? C. FeCl.sub.36H.sub.2O 2,6-lutidine ?-terpinene 24 h 70% (10%) (1.2) (1.2) MeCN 90? C. FeCl.sub.2 2,6-lutidine ?-terpinene 24 h 67% (10%) (1.2) (1.2) MeCN 90? C. Fe(acac).sub.3 2,6-lutidine ?-terpinene 24 h 71% (10%) (1.2) (0.5) MeCN 90? C. Fe(acac).sub.3 2,6-lutidine ?-terpinene 24 h 49% (20%) (1.2) (1.2) MeCN 90? C. Fe(acac).sub.3 2,6-lutidine ?-terpinene 24 h 35% (2%) (1.2) (1.2) Toluene 90? C. Fe(acac).sub.3 2,6-lutidine ?-terpinene 24 h 36% (10%) (1.2) (1.2) Dichloroethane 90? C. Fe(acac).sub.3 2,6-lutidine ?-terpinene 24 h 59% (10%) (1.2) (1.2) Dimethylformamide 90? C. Fe(acac).sub.3 2,6-lutidine ?-terpinene 24 h 35% (10%) (1.2) (1.2) MeCN 70? C. Fe(acac).sub.3 2,6-lutidine ?-terpinene 24 h 20% (10%) (1.2) (1.2) MeCN 100? C. Fe(acac).sub.3 2,6-lutidine ?-terpinene 24 h 79% (10%) (1.2) (1.2) MeCN 90? C. Fe(acac).sub.3 2,6-lutidine ?-terpinene 48 h 84% (10%) (1.2) (1.2)

[0300] Using the described conditions, several plasmodione derivatives diversely substituted at the menadione core were synthesised from the corresponding menadione derivatives, substituted at C-6, C-7, or C-8, or disubstituted at C-6 and C-7 (scheme) (Donzel M., Elhabiri M., Davioud-Charvet E. A bioinspired photoredox benzylation of quinones. J. Org. Chem. 2021, 86, 10055-10066. doi: 10.1021/acs.joc.1c00814).

##STR00088##

TABLE-US-00002 TABLE Yields obtained during the synthesis of different plasmodione derivatives under photoredox conditions. Yield (%) [00089] 32 [00090] 46 [00091] 55 [00092] 61 [00093] 44.sup.a [00094] 51 .sup.areaction time is 50 h instead of 24 h

Example 44: 3,5-dimethyl-2-{[4-(trifluoromethyl)phenyl]methyl}naphthalene-1,4-dione (LL010)

[0301] ##STR00095##

[0302] According to the general procedure, 2,8-dimethyl-1,4-dihydronaphthalene-1,4-dione (Rodo E. C., Feng L., Jida, M., Ehrhardt K., Bielitza M., Boilevin J., Lanzer M., Williams D. L., Lanfranchi, D. A., Davioud-Charvet, E. A platform of regioselective methodologies to access to polysubstituted 2-methyl-1,4-naphthoquinones derivatives: scope and limitations. Eur. J. Org. Chem. 2016, 11, 1982-1993. doi: 10.1002/ejoc.201600144) and 4-(trifluoromethyl)benzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=7:3, UV), 31 mg (0.089 mmol, 32% yield) of LL010 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) 8.01 (dd, J=7.6 Hz, 1.5 Hz, 1H), 7.60-7.47 (m, 4H), 7.34 (d, J=8.4 Hz, 2H), 4.06 (s, 2H), 2.74 (s, 3H), 2.22 (s, 3H). .sup.19F NMR (377 MHz, Chloroform-d) ? ?62.48 (s). .sup.13C NMR (101 MHz, Chloroform-d) ? 187.2, 185.0, 146.3, 143.0, 142.5, 141.2, 137.7, 133.5, 132.9, 130.0, 129.0, 128.9 (q, J=32.5 Hz), 125.7, (q J=3.7 Hz), 125.5, 124.3 (q, J=271.8 Hz), 32.3, 23.0, 13.8.

Example 45: 3,6-dimethyl-2-{[4-(trifluoromethyl)phenyl]methyl}naphthalene-1,4-dione (LL012)

[0303] ##STR00096##

[0304] According to the general procedure, 2,7-dimethyl-1,4-dihydronaphthalene-1,4-dione (Rodo E. C. et al., Eur. J. Org. Chem. 2016, 11, 1982-1993) and 4-(trifluoromethyl)benzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=7:3, UV), 43 mg (0.13 mmol, 46% yield) of LL012 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.99 (dd, J=7.9 Hz, 5.2 Hz 1H), 7.91-7.87 (m, 1H), 7.54-7.48 (m, 3H), 7.34 (d, J=8.0 Hz, 2H), 4.07 (s, 2H), 2.48 (d, J=8.0 Hz, 3H), 2.23 (s, 3H). .sup.19F NMR (377 MHz, Chloroform-d) ? ?62.48 (s). .sup.13C NMR (101 MHz, Chloroform-d) ? 186.6, 184.5, 144.9, 144.7, 144.5, 144.3, 142.5, 134.5, 132.1, 129.8, 129.0, 128.9 (q, J=32.5 Hz), 126.9, 125.7 (q, J=3.8 Hz), 124.3 (q, J=271.8 Hz) 32.4, 21.0, 13.4.

Example 46: 2,7-dimethyl-3-{[4-(trifluoromethyl)phenyl]methyl}naphthalene-1,4-dione (LL015)

[0305] ##STR00097##

[0306] According to the general procedure, 2,6-dimethyl-1,4-dihydronaphthalene-1,4-dione (Rodo E. C. et al., Eur. J. Org. Chem. 2016, 11, 1982-1993) and 4-(trifluoromethyl)benzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=7:3, UV), 30 mg (0.086 mmol, 55% yield) of LL015 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.99 (d, J=7.9 Hz, 1H), 7.89-7.88 (m, 1H), 7.55-7.46 (m, 3H), 7.34 (d, J=7.7 Hz, 2H), 4.07 (s, 2H), 2.48 (s, 3H), 2.24 (s, 3H). .sup.19F NMR (377 MHz, Chloroform-d) ? ?62.49 (s). .sup.13C NMR (101 MHz, Chloroform-d) ? 185.1, 184.9, 145.0, 144.9, 144.3, 142.5, 134.5, 132.0, 130.0, 129.0, 128.9 (q, J=32.3 Hz), 127.0, 126.8, 125.7 (q, J=3.9 Hz), 124.1 (q, J=272.9 Hz), 32.5, 22.0, 13.5.

Example 47: 6-fluoro-3-methyl-2-{[4-(trifluoromethyl)phenyl]methyl}naphthalene-1,4-dione (LL016)

[0307] ##STR00098##

[0308] According to the general procedure, 7-fluoro-2-methyl-1,4-dihydronaphthalene-1,4-dione (Rodo E. C. et al., Eur. J. Org. Chem. 2016, 11, 1982-1993) and 4-(trifluoromethyl)benzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=7:3, UV), 32 mg (0.092 mmol, 61% yield) of LL016 were isolated as a yellow solid. .sup.1H NMR (400 MHz, Chloroform-d) 8.13 (dd, J=8.6 Hz, 5.2 Hz, 1H), 7.74 (dd, J=8.5, 2.6 Hz, 1H), 7.53 (d, J=7.9 Hz, 2H), 7.41-7.31 (m, 3H), 4.08 (s, 2H), 2.26 (s, 3H). .sup.19F NMR (377 MHz, Chloroform-d) ? ?62.51 (s), ?102.18 (td, J=8.4 Hz, 5.2 Hz). .sup.13C NMR (101 MHz, Chloroform-d) ? 184.2 (d, J=1.7 Hz), 183.4, 166.2 (d, J=257.1 Hz), 145.1 (d, J=2.0 Hz), 144.8, 142.1 (d, J=1.5 Hz), 134.8 (d, J=8.0 Hz), 130.0 (d, J=8.8 Hz), 129.1 (d, J=32.4 Hz), 128.6 (d, J=3.3 Hz), 125.8 (q, J=3.7 Hz), 124.3 (q, J=272.0 Hz), 121.0 (d, J=22.5 Hz), 113.2 (d, J=23.5 Hz), 32.5, 13.5.

Example 48: 6,7-dimethoxy-2-methyl-3-{[4-(trifluoromethyl)phenyl]methyl}naphthalene-1,4-dione (LL013)

[0309] ##STR00099##

[0310] According to the general procedure, 6,7-dimethoxy-2-methyl-1,4-dihydronaphthalene-1,4-dione (Rodo E. C. et al., Eur. J. Org. Chem. 2016, 11, 1982-1993) and 4-(trifluoromethyl)benzyl bromide were used. After chromatography on silica gel (Toluene/AcOEt=95/5, UV), 37 mg (0.095 mmol, 44% yield) of LL013 were isolated as an orange solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.56-7.48 (m, 4H), 7.34 (d, J=8.0 Hz, 2H), 4.05 (s, 2H), 4.02 (s, 3H), 4.00 (s, 3H), 2.22 (s, 3H). .sup.19F NMR (377 MHz, Chloroform-d) ? ?62.47 (s). .sup.13C NMR (101 MHz, Chloroform-d) ? 184.7, 184.1, 153.48, 153.45, 144.4, 143.9, 142.6, 129.0, 128.9 (q, J=32.4 Hz), 127.0, 126.7, 125.7 (q, J=3.7 Hz), 124.3 (q, J=272.7 Hz), 108.1, 107.9, 56.6, 56.5, 32.5, 13.4.

Example 49: 2,6,7-trimethyl-3-{[4-(trifluoromethyl)phenyl]methyl}naphthalene-1,4-dione (LL008)

[0311] ##STR00100##

[0312] According to the general procedure, 2,6,7-trimethyl-1,4-dihydronaphthalene-1,4-dione (Rodo E. C. et al., Eur. J. Org. Chem. 2016, 11, 1982-1993) and 4-(trifluoromethyl)benzyl bromide were used. After chromatography on silica gel (Cyclohexane:Toluene=2:3, UV), 45 mg (0.13 mmol, 51% yield) of LL008 were isolated as an orange solid. .sup.1H NMR (400 MHz, Chloroform-d) 7.83 (d, J=4.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 7.37-7.30 (m, 4H), 4.06 (s, 2H), 2.39 (s, 3H), 2.38 (s, 3H), 2.22 (s, 3H). .sup.19F NMR (377 MHz, Chloroform-d) ? ?62.47 (s). .sup.13C NMR (101 MHz, Chloroform-d) ? 185.5, 184.9, 144.7, 144.2, 143.57, 143.55, 142.6, 130.3, 130.0, 129.0, 128.9 (q, J=32.6 Hz), 127.7, 127.5, 125.7 (q, J=3.8 Hz), 124.3 (q, J=273.4 Hz), 32.4, 20.3, 13.4.