Visible light-promoted Selectfluor-mediated quinone functionalization with unactivated Csp 3 -H components

A visible light-promoted metal-free cross-dehydrogenative-coupling (CDC) method for the alkylation of 1,4-naphthoquinones is reported using Selectfluor as a hydrogen atom transfer (HAT) agent. This protocol is suitable for a variety of 1,4-naphthoquinones and Csp 3 -H compounds and it facilitates the formation of pharmaceutically important quinone scaffolds under mild conditions. Using this methodology, the antimalarial drug, parvaquone, was synthesized in a single step.

Owing to the importance of alkylated 1,4-quinone frameworks, several radical alkylation protocols for the functionalization of 1,4-quinones have been proposed in recent years (Scheme 1).For instance, Molander and co-workers reported alkylation of 1,4-quinones via oxidative homolysis of 1,4-dihydropyridines (Scheme 1a). 11iu's group developed an Fe(III) mediated radical alkylation of quinones with olefins (Scheme 1b). 12Baxter and co-workers reported a silver-catalysed radical alkylation of quinones (Scheme 1c). 13Also, a persulfate mediated alkylation of 1,4-quinones using carboxylic acids 14 and a copper catalysed direct cross-coupling of 1,4-quinones with cycloalkanes 15 were demonstrated by Lee's group (Scheme 1d).Nevertheless, each of these methods has limitations such as pre-functionalization of the alkyl partner, requirement of transition metal reagents and explosive peroxides as oxidants.Hence, more efficient, milder and sustainable methods are still desirable.
Visible light-promoted Selectfluor-mediated direct functionalization of C-H bonds via the hydrogen atom transfer (HAT) mechanism has attracted attention in recent years.Pioneering work by Lei's group [16][17] demonstrated the Csp 3 -H heteroarylation of cycloalkanes, ethers and alcohols mediated by Selectfluor under visible-light irradiation.At the same time, Jin's group 18 used similar reaction conditions for the alkylation of heteroarenes via the generation of alkyl radicals from unactivated Csp 3 -H components.However, a visible light-promoted, Selectfluor-mediated C-H functionalization for the alkylation of quinones has not yet been studied.Herein, we report a new method of introducing alkyl groups into the 1,4-naphthoquinone skeleton without pre-functionalization of the alkyl partner (Scheme 1e).This method utilizes visible light and the green oxidant Selectfluor without the requirement for radical initiator or transition metal photocatalyst.

Results and Discussion
With an overall aim of developing a direct Csp 2 -Csp 3 cross coupling strategy for the alkylation of quinones under mild conditions, we started our investigation by irradiating a mixture of 2-acetoxy-1,4-naphthoquinone (1a), cyclohexane (2a) and Selectfluor in acetonitrile under a N2 atmosphere at room temperature using a Penn PhD photoreactor M2 (blue LED, 450 nm) (Table 1, entry 1).
To our delight, the desired cross coupled product 3a was formed in 42% yield within one hour.No desired product was observed when the light source was changed to 14 W white LED (Table 1, entry 2).Also, heating the reaction mixture to 80 o C in the absence of light, also did not yield any of the desired product (Table 1, entry 3).Use of additives such as AcOH and TFA didn't improve the yield of 3a (Table 1, entries 4 and 5) and Et3N completely diminished the yield of 3a (Table 1, entry 8).Use of the solvent acetone led to lower yield of 3a (Table 1, entry 6) and reaction didn't take place when cyclohexane was used as a solvent (Table 1, entry 7).Finally, when quinone 1a was added to a mixture of cyclohexane and Selectfluor over a period of 20 minutes through syringe pump, the isolated yield of 3a was improved to 54% (Table 1, entry 10).The scope and generality of this cross-coupling strategy was then investigated using various 1,4-quinones and aliphatic C-H components under the optimized conditions (Table 2).The reaction of 2-hydroxy-1,4naphthoquinone with cyclohexane under the optimized conditions afforded the antimalarial drug molecule parvaquone (3b) in 42% yield.1,4-Naphthoquinone bearing a CF3 group at the 2-position reacted smoothly and furnished the desired product (3c) in 55% yield.Whereas, 2-methyl-and 2-methoxy-1,4-napthoquinones afforded the desired products (3d and 3e) in lower yields.Unsubstituted 1,4-naphthoquinone gave the desired product 3f in 46% yield.p-Benzoquinone did not afford the desired product and its complete decomposition was observed under the reaction conditions.Next, the scope of different aliphatic C-H components was examined using 2-hydroxy-1,4-naphthoquinone as reaction partner.The reaction with cycloalkanes such as cyclopentane and cyclooctane was successful and furnished the desired alkylated quinones (3h and 3i) in moderate yields.Later, a series of methylbenzenes were investigated.Toluene, m-xylene, p-xylene and mesitylene were all found to be suitable substrates for this methodology and furnished the desired compounds (3j-3m).Notably, ortho-bromotoluene reacted well without loss of Br giving 3n, thus affording the potential for further cross-couplings.In addition, cyclic ether 1,4-dioxane was also a competent substrate, giving the desired product (3o) in 47% yield.
To gain mechanistic insight, we next performed radical inhibition experiments (Scheme 2).When the reaction of 2-hydroxy-1,4-naphthoquinone with toluene was conducted in the presence of three equivalents of TEMPO and butylated hydroxytoluene (BHT) (2,6-bis(1,1-dimethylethyl)-4-methylphenol) under the standard conditions, formation of the product 3j was completely suppressed.These experiments clearly indicate a radical reaction pathway.

AUTHOR(S) Scheme 2. Radical inhibition experiments.
][17] Firstly, the N-radical cation B formed by the homolytic fission of Selectfluor A abstracts a hydrogen atom from the alkane 2 to give the alkyl radical intermediate D and dication C. The generated nucleophilic alkyl radical D adds to the electron-deficient quinone 1 to give the radical intermediate E. Finally, abstraction of a hydrogen atom by fluorine radical from intermediate E generates the product 3 (Scheme 3).
Plausible reaction mechanism for the alkylation.

Conclusions
In conclusion, we have developed a visible-light induced, Selectfluor mediated Csp 2 -Csp 3 cross coupling strategy without the need of prefunctionalization of Csp 3 partner for the alkylation of 1,4-naphthoquinones.This mild protocol is suitable for various 1,4-naphthoquinones and aliphatic Csp 3 -H components to afford pharmaceutically important quinone frameworks in moderate yields.

Experimental Section
General.Unless otherwise noted, reagents obtained from commercial suppliers were used without further purification.Reactions were monitored using thin-layer chromatography (SiO2).Thin layer chromatography was performed on Merck silica gel plates and visualized by UV light.Column chromatography was carried out using silica gel (100-200 mesh) packed in glass columns.NMR spectra were recorded at 300, 400, 500 MHz (H) and at 75, 100, 125 MHz (C), respectively.Chemical shifts (δ) are reported in ppm, using the residual solvent peak in CDCl3 (H: δ = 7.26 and C: δ = 77.0ppm) as internal standard, and coupling constants (J) are given in Hz.
HRMS were recorded using ESI-TOF techniques.Melting points of solids were recorded using Electrothermal (IA9100) melting point apparatus.Irradiation was performed with Penn PhD photoreactor M2 (PR M2) (blue LED, 450 nm) purchased from Sigma-Aldrich.
General procedure for the synthesis of alkylated 1,4-naphthoquinones.Selectfluor (0.4 mmol) and aliphatic Csp 3 -H component 2 (2.0 mmol) were weighed in a vial with rubber septum and MeCN (1.0 mL) was added to this mixture.The vial was back filled with N2 and it was introduced into Penn PhD photoreactor M2 (blue LED 450 nm).To this mixture, a solution of 1,4-naphthoquinone 1 (0.2 mmol) in MeCN (1.0 mL) was added over a period of 20 min through syringe pump.After completion of reaction (1 h), the reaction mixture was concentrated using rotary evaporation and the crude reaction mixture was purified by column chromatography to get the desired compound 3.