Iron catalyzed C–C dehydrogenative coupling reaction: synthesis of arylquinones from quinones/hydroquinones

An atom-economical approach for the synthesis of arylquinones was achieved successfully via direct oxidative C–C dehydrogenative coupling reaction of quinones/hydroquinones with electron-rich arenes using an inexpensive Fe–I2–(NH4)2S2O8 system. The efficiency of this catalytic approach was established with a broad scope of substrates involving quinones and hydroquinones to give high yields (60–89%) of several arylated quinones. The present protocol is simple, practical, and shows good functional group tolerance.


Introduction
Quinone scaffolds are widely distributed in natural products and gained importance owing to their roles in biological systems, 1 and were utilized as intermediates in materials, 2 bioinspired synthetic products, 3 and biosynthesis. 4 They are also involved in many bioenergetic processes due to their electron transport properties. 5 Of particular importance, aryl substituted quinones possess unique electronic properties, 6 which have several applications in chemistry and many natural products. For example, Belamcanda chinensis, were used as a specic cyclooxygenase inhibitor, belamcandaquinones A and B isolated from the seed of a medicinal plant. 7 Furthermore, aryl-substituted quinones are very useful in the dye industry owing to their important coloring properties. 8 Thus, the synthesis of aryl substituted quinones has attracted signicant attention and many methods have been developed.
Several approaches were described for the synthesis of arylated quinones involving different types of starting materials. Utilized of prefunctionalized quinones and arenes requires the presence of expensive transition metal reagents. Examples include the transition-metal-catalyzed coupling of a stannylquinone with an arylhalide, 9 haloquinone with a styrylstannane 10 and halogenated quinones with boronic acids. 11 Heck type arylation oen comprises unfunctionalized quinones and pre-functionalized arenes. Commercially available, but costly arylboronic acids were used in such transformations, in the presence of metal reagents made of such as Ag, Rh, Ir, Pd, and Fe salts. 12 Furthermore, several metal free methods using diazonium salt-hydrazine catalysts, diazonium salts, diaryliodonium salts, and arylhydrazine salts have also been described. 13 On the other hand, oxidative C-H/C-H coupling assembling a diverse variety of complex aromatic systems was also employed in coupling of quinones and arenes. Such C-H/ C-H coupling was carried out in the presence of metal salts such as In(OTf) 3 , Pd(OAc) 2 , Rh salts, Pd(TFA) 2 ,and FeCl 3 . 14 In general, the arylation of quinones compounds with carbon nucleophiles is achieved through Michael-type 1,4conjugate addition reaction of electron-rich arenes 15 or through the transition-metal-catalyzed coupling reactions. However, arene-quinone coupling have certain limitations, such as organometallic reagents generated from prefunctionalized starting material, aryl radicals obtained from prefunctionalized arenes and expensive transition metals. Hence, a 1,4-conjugate addition reaction followed by oxidation is a preferred route for the arylation reactions of quinones and, based on this concept, a few metal-catalyzed reactions were reported. Despite these advances, efforts still need to be made in terms of mild reaction conditions, inexpensive reagents, and wide substrate scope. 16a We have already reported the coupling of indoles and quinones in the absence of any catalyst, 16c but herein we add a catalyst to expand the scope and perform the coupling not only with indoles but also with other arenes. In consideration of these important points and continuing our research interest on functionalized of quinone derivatives, we wish to report a sequential one-pot approach to arylated quinones through direct oxidative C-C dehydrogenative coupling reaction of quinones/hydroquinones with electron-rich arenes using an inexpensive Fe-I 2 -(NH 4 ) 2 S 2 O 8 system (Scheme 1).
the direct oxidative C-C dehydrogenative coupling reaction of quinones/hydroquinones with electron-rich arenes (see Table 1, as well as ESI †). Fortunately, under the reaction of Fe (10 mol%), oxidant (NH 4 ) 2 S 2 O 8 (2.0 equiv.) and DCE (2 mL), at 100 C, for 24 h (Table 1, entry 1), the desired product 3a was obtained in 58% isolated yield. Other metal salts did not provide better results including FeSO 4 $7H 2 O, FeCl 3 , Zn, and Pd(OAc) 2 also tested for the cross-coupling (entries 2-5, see ESI †). When the quantity of the catalyst (Fe) was increased to 20 mol% (entry 6), the yield of the product 3a increased (65%). Among the various additives screened, I 2 was the most efficient (entries 8-10, see ESI †). Subsequently, the oxidant was screened. (NH 4 ) 2 S 2 O 8 was proved to be more efficient than others, such as K 2 S 2 O 8 and Oxone (entries 11-12, see ESI †). Furthermore, when the temperature was raised to 120 C, the yield increased to 89% (entry 14). It should be noted that increasing or decreasing the reaction temperature gave slightly inferior results, indicating that the transformation was sensitive to temperature (see ESI †). Based on these results, the best yield of 3a was obtained from the reaction of 2a (2 equiv.) and Fe (20 mol%), additive I 2 (20 mol%), oxidant (NH 4 ) 2 S 2 O 8 (2 equiv.) in DCE at 120 C under sealed tube.
With the optimized reaction conditions in hand, we next set out to explore the universality of this method ( Table 2). Therefore, a series of electron-rich arenes with quinones, including anilines and indole derivatives, were subjected to this process. Subsequently, we evaluated the scope and the inuence of the substituents on the electron-rich arenes moiety. A series of disubstituted anilines, such as dialkyl, dibenzyl, diallyl, and cycloalkylamine compounds, were examined and the desired arylated products obtained in high yields (3a-3j). The scale-up of the reaction was performed to reveal the applicability of this method. When 1,4-naphthoquinone 1a was scaled up by 5 mmol, 3a was isolated in 85% yield. When the benzyl group Scheme 1 Approaches to arylated quinones compounds. was attached to the N of the aniline, the product was obtained in excellent yield (3c). The exciting thing was that this protocol showed good compatibility with carbon-carbon double bonds (3d). Interestingly, the cyclic aniline compounds were capable of obtaining the corresponding products in good yields (3j). Monosubstituted aniline derivatives were converted into the respective products in moderate to good yields (3k and 3l).
Although there is a possibility of NH-attack on quinones, we exclusively observed the C-C products. When we carried out the reaction with a meta-meta-substituted N,N-dimethylaniline as a substrate, we were also able to obtain an arylated product, albeit at a moderate yield (3m), wherein the methyl group could hamper the coupling. It was possible that the steric hindrance effect of the meta positions and led to a decrease in yield. Heterocyclic compounds, such as indoles (C-3) were successfully arylated under the optimized conditions (3n-3q). It is noteworthy that electron withdrawing indoles (2o) with a substituent at the 2-position also proved to be suitable coupling partners to provide the corresponding products 3o in 62% yield with a catalyst, but 3o was obtained in traces in the absence of Fe/iodine system. 16c At the beginning, Fe and I 2 gives FeI 2 under the conditions of heating. FeI 2 coordinates to the carbonyl oxygen of the 1,4-naphthoquinone, which increases the electrophilicity and assists 1,4-conjugative addition. Thus, Fe/iodine system can accelerate the reaction and increase the yield. We then proceeded to study the scope of quinone derivatives. We hypothesize that the sensitive chlorine at the bposition of naphthoquinone was compatible with the reaction conditions, which can easily be transformed further by crosscoupling reactions. Anthraquinone 1s was also employed, affording the corresponding product 3s in 83% yield. Subsequently, the synthesis of arylated quinones for a broad substrate scope involved hydroquinone with various electronrich arenes. As shown in Table 3, moderate to good yields of arylated quinones were obtained upon reacting 1,4 hydroquinone with various electron-rich arenes having disubstituted anilines, as in the case of dialkyl, dibenzyl and cycloalkylamine Table 2 Substrate scope for quinones with anilines a a Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), Fe (20 mol%), I 2 (20 mol%), (NH 4 ) 2 S 2 O 8 (2 equiv.), DCE (2 mL), 120 C, sealed tube for 24 h. Isolated yield. Bn means benzyl. b In a 5 mmol scale. Table 3 Substrate scope for hydroquinone with anilines a a Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol), Fe (20 mol%), I 2 (20 mol%), (NH 4 ) 2 S 2 O 8 (2 equiv.), DCE (2 mL), 120 C, sealed tube for 24 h. Isolated yield. Bn means benzyl.
compounds. Monosubstituted aniline derivatives were converted into the respective products in moderate yields (3l). When we carried out the reaction with a meta-substituted N,Ndimethylaniline as a substrate, we were also able to obtain an arylated product, albeit at a moderate yield (3m). Heterocyclic compounds, such as indoles (C-3) were successfully arylated under the optimized conditions (3n and 3q).
Next, to gain understanding about the mechanism, control experiments were carried out (Scheme 2). The studies revealed that the radical scavenger BHT (2,6-di-tert-butyl-4-methylphenol) did not inhibit the reaction under standard conditions, ruling out the radical mechanism (Scheme 2a). The reaction between compounds 1a and 2a generated the coupling product 3a in a yield of 37% in the absence of (NH 4 ) 2 S 2 O 8 (Scheme 2b). The studies demonstrated the importance of (NH 4 ) 2 S 2 O 8 . And the reaction of model compounds 1a and 2a generated the coupling product 3a without Fe and I 2 in a yield of 34% (Scheme 2c). The corresponding product 3a is formed in 41% and 52% yield respectively in the presence of (NH 4 ) 2 S 2 O 8 with Fe or I 2 (Scheme 2d and 2e), which showed that the Fe and I 2 played a pivotal role in obtaining the desired product. The corresponding product 3a is formed in 67% yield in the presence of (NH 4 ) 2 S 2 O 8 with FeI 2 (Scheme 2f).
On the basis of this and previous reports, 16 a possible reaction mechanism was proposed (Scheme 3). At the beginning, we hypothesize that Fe and I 2 gives FeI 2 under the conditions of heating. The reaction starts with the in situ oxidation of hydroquinone (4a) to 1,4-naphthoquinone (1a) over a (NH 4 ) 2 S 2 O 8 oxidant. Then, FeI 2 coordinates to the carbonyl oxygen of the 1,4-naphthoquinone, which increases the electrophilicity and assists 1,4-conjugate addition. Due to nucleophilic nature of the electron-rich arenes 2a, it would be attracted to the electrophilic C-2 positions of naphthoquinone, and subsequently, 1,4-addition of the

Conclusions
In conclusion, we have successfully demonstrated ironmediated oxidative C-H/C-H cross-coupling reaction between quinones/hydroquinones and various electron-rich arenes to accomplish the arylated quinones using an inexpensive Fe-I 2 -(NH 4 ) 2 S 2 O 8 system. The signicant aspects of our work allows modest functional group tolerance, including quinones and hydroquinones.

Experimental section
To a solution of DCE (2 mL) was added 1 or 4a (0.3 mmol), 2 (0.8 mmol), Fe (0.06 mmol, 20 mol%), I 2 (0.06 mmol, 20 mol%), and (NH4) 2 S 2 O 8 (0.6 mmol, 2 equiv.). The reaction mixture was stirred at 120 C for 24 h. Aer the completion of the reaction (monitored by TLC). The reaction was quenched with saturated salt water (2 mL) and the mixture was extracted with EtOAc (3 Â 3 mL). The organic extracts were washed with brine, dried over Na 2 SO 4 , ltered and the solvent was removed in vacuo. The crude product was puried by silica gel column chromatography to give 3.

Conflicts of interest
There are no conicts to declare.