K₂S₂O₈-mediated metal-free direct C–H functionalization of quinones using arylboronic acids

Abstract

Direct C–H functionalization of quinones with arylboronic acids is achieved using K₂S₂O₈ as the sole and efficient green catalytic system. This method provides a straightforward and sustainable way to construct arylquinones via a radical pathway in moderate to good yields under metal-free conditions.

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Introduction

Arylated benzoquinone, naphthoquinone and heterocyclic ring systems form important skeletal frameworks of several biologically active compounds and natural products (Fig. 1).^1a–d Unique electronic and visual properties of arylated quinones make them act as useful dyes and photoactive materials.^2a,b Recent developments on C–C bond forming methods made it possible to carryout direct C–H functionalization of quinones using different aryl counter parts. Consequently, several new procedures have been reported for the synthesis of arylated quinones. Employing stannyl quinones for Stille type coupling^3a or halogenated quinones for Suzuki–Miyaura type coupling^3b have their own drawbacks as they require pre-functionalization of quinones. Haloquinones or stannyl quinones are hard to access due to chemo and regioselectivity issues. Heck type cross coupling fails in the case of quinones due to the fact that quinones can coordinate with Pd and usually acts as a catalyst for reoxidation of Pd(0) species^4a,b

Fig. 1 Bioactive arylquinone motifs.

Direct C–H/C–H cross coupling is highly advantageous, as this avoids the involvement of functionalized starting materials. Rh(III) together with an expensive re-oxidant (AgSbF₆–AgOAc) worked well for C–H/C–H coupling of quinones when used in combination with a directing group.⁵ Similarly, a stoichiometric quantity of Pd(OAc)₂ or a catalytic quantity of Pd(OAc)₂–Na₂S₂O₈ was used for direct C–H/C–H cross coupling.^6a Pd(acac)₂ with a large excess of Ag₂CO₃ as a co-oxidant was found useful for the synthesis of arylated quinone from hydroquinone.^6b Pd(TFA)₂ with (NH₄)₂S₂O₈ as the co-oxidant is yet another useful catalytic system reported for arylation of quinones as well as olefins.^6c Direct C–H/C–H cross coupling is mainly applicable for electron rich aryl counterparts, thus making it substrate specific^5,6a,c and less attractive.

Arylation of quinones using a radical is a successful approach. Although Meerwein arylation of quinone was reported earlier,^7a,b improved methods were reported only later. It requires hydroquinone or a reducing metal like copper for the homolytic decomposition of diazonium functionality to form an aryl radical. Aryl diazonium salts are very unstable, sometimes explosive above 0 °C and require highly acidic conditions for their synthesis, thus not suitable for large scale applications.^7c Recently, application of metal-free methods for making C–C or C–heteroatom bonds gained the attention of chemists.⁸ However, methods involving metal-free generation of radicals are scarce.⁹ Aryl radicals obtained from phenyl hydrazine-IBX were used for arylation of naphthoquinones to obtain products in moderate to good yields.^9a Different Ar₂IOTf salts were also used successfully to generate aryl radicals for arylation of benzoquinone and naphthoquinone.^9b The scarce availability of substituted phenyl hydrazine and Ar₂IOTf salts makes these approaches of limited substrate scope and hence less attractive.

Arylboronic acids are highly stable, even in water and are readily available in a variety of substituted forms, making it a convenient precursor for building compounds of wide substrate scope. After Molina et al. demonstrated that naphthoquinones can be directly arylated using arylboronic acids in the presence of a Pd/Cu catalyst and a FeCl₃ co-oxidant,¹⁰ a series of reports appeared on the application of arylboronic acids for arylation of quinones using different metal salts such as AgNO₃,^11a FeS,^11b FeNO₃,^11c FeSO₄,^11d and Fe(acac)₂,^11e all in combination with a large excess of K₂S₂O₈ as the co-oxidant. Pd(OCOCF₃)₂ with a large excess of 2,6-dichlorobenzoquinone (2.5 equiv.) as the co-oxidant was also reported for the diarylation of quinones using arylboronic acids.¹² Analysis of methods reported so far reveals that except for few reagents (IBX and Ar₂IOTf)^9a,b almost all the methods reported require metal salts and a re-oxidant (Scheme 1).

Scheme 1 Arylation of quinones.

It is well known that K₂S₂O₈ decomposes at higher temperature to generate radicals.^13a,b However, in the presence of metal salts, decomposition of K₂S₂O₈ takes place at room temperature to generate sulphate radicals.^11d,14 Thus we envisaged that an aryl radical could be generated from arylboronic acids using K₂S₂O₈ at higher temperature and used for arylation of quinones. K₂S₂O₈ is a versatile oxidant available at much cheaper price and can be used for the regeneration of quinone from hydroquinone. Avoiding metallic reagents is advantageous in terms of elimination of metal toxicity, cost saving and minimization of environmental pollution. Herein, we present a simple method for arylation of quinones and heterocycles using arylboronic acid under metal free conditions.

Results and discussion

Our studies began with optimization of conditions for the reaction between quinone 1a (1.0 equiv.) and arylboronic acid 2a (1.5 equiv.) in the presence of K₂S₂O₈ as an oxidant in DCE/H₂O. Various reaction parameters were studied and the results are summarized in Table 1. No reaction was observed at room temperature (rt) with 1.0 equiv. of K₂S₂O₈, in DCE. However when the solvent system was changed to DCE/H₂O, we were delighted to see the formation of 3a in traces (entry 2). Increase in temperature to 80 °C lead to formation of product 3a in 30% isolated yield (entries 1 and 3). It was concluded that temperature is the key factor for the reaction to take place. Increasing the amount of K₂S₂O₈ to 2.0 equiv. had a beneficial effect and the product 2a was obtained in the highest yield (72%) in the shortest reaction time (entry 4). Further, increase in the quantity of K₂S₂O₈ to 3.0 equiv. had no improvement on the yield (entry 5). However, when the quantity of K₂S₂O₈ was increased further to 5.0 equiv. the yield of the product 3a decreased (entry 6). Similarly, increasing or decreasing the temperature from 80 °C only provided the product 3a in low yield (entries 7 and 8). Likewise, when the quantity of arylboronic acid 2a was decreased to 1.0 equiv. the yield decreased (entry 9). In the absence of K₂S₂O₈ no desired product was formed, indicating that K₂S₂O₈ is crucial to this reaction (entry 10). Other oxidants such as TBHP, H₂O₂ and Oxone as catalysts were ineffective for the reaction (entries 11–13). Among the different solvent systems, DCE : H₂O furnished the highest yield (entries 14–18). Thus a systematic screening study revealed that 1 (1.0 equiv.), 2a (1.5 equiv.) and K₂S₂O₈ (2.0 equiv.) in DCE–H₂O at 80 ^°C are the optimum conditions for arylation.

Table 1 Optimization studies for the formation of 3a

S.NO	Additive	Solvent	Temp (°C)	Time	Yield^a (%)
a Isolated yield. b No reaction. c 2a (1.0 mmol).
1	K2S2O8 (1.0 equiv.)	DCE	rt	24 h	nr^b
2	K2S2O8 (1.0 equiv.)	DCE/H2O	rt	24 h	5
3	K2S2O8 (1.0 equiv.)	DCE/H2O	80	24 h	30
4	K 2 S 2 O 8 (2.0 equiv.)	DCE/H 2 O	80	1 h 30 min	72
5	K2S2O8 (3.0 equiv.)	DCE/H2O	80	1 h 10 min	72
6	K2S2O8 (5.0 equiv.)	DCE/H2O	80	1 h	65
7	K2S2O8 (2.0 equiv.)	DCE/H2O	60	2 h	60
8	K2S2O8 (2.0 equiv.)	DCE/H2O	100	1 h	64
9	K2S2O8 (2.0 equiv.)	DCE/H2O	80	2 h 30 min	58^c
10	—	DCE/H2O	80	24 h	nr^b
11	TBHP (2.0 equiv.)	DCE/H2O	80	24 h	nr^b
12	H2O2 (2.0 equiv.)	DCE/H2O	80	24 h	nr^b
13	Oxone (2.0 equiv.)	DCE/H2O	80	24 h	nr^b
14	K2S2O8 (2.0 equiv.)	H2O	80	24 h	36
15	K2S2O8 (2.0 equiv.)	DMF/H2O	80	1 h 50 min	45
16	K2S2O8 (2.0 equiv.)	Toluene/H2O	80	24 h	50
17	K2S2O8 (2.0 equiv.)	DMSO/H2O	80	24 h	nr^b
18	K2S2O8 (2.0 equiv.)	MeOH/H2O	80	24 h	Trace

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With the optimal condition in hand, the scope of quinone arylation reaction was explored on different substrates (Scheme 2). Different arylboronic acids, bearing electron donating groups 2b–2e reacted well with 1,4-benzoquinone to give the corresponding products 3ab–3ae in moderate to good yields. Similarly, arylboronic acids 2f and 2g containing substituents at the sterically crowded ortho position reacted fast to furnish the products 3af and 3ag in moderate yield. Arylboronic acids, 2h–2j bearing halogen groups were well tolerated and offered 3ah–3aj in moderate to good yields. Next, the effect of the substituent on quinone was investigated. Mono substituted benzoquinone such as 2-methylcyclohexa-2,5-diene-1,4-dione (1b) produced a regio isomeric mixture of arylated quinones 3bka and 3bkb in 72% overall yield. Similarly, more sterically hindered 2,6-dimethoxybenzoquinone (1c) reacted successfully with different aryl boronic acids 2a, 2b, 2h, and 2j to provide the corresponding products 3cl–3co in good yields. However, 2,6-dimethylbenzoquinone (1d) and 2,5-dichlorobenzoquinone (1e) delivered the desired products 3dp, 3dq (inseparable mixture along with starting material) and 3er respectively in low yield. The (4-cyanophenyl)boronic acid (2s) containing a strong electron withdrawing –CN group on reaction with simple benzoquinone (1a) failed to produce the desired product 3as. This may be due to the unstable nature of the cyano aryl radical.^11a Similarly, 2,6-dihydroxybenzoquinone (1f) and t-butylbenzoquinone (1g) on treatment with phenylboronic acid (2a) also failed to produce the expected arylated products 3t and 3u, even after a prolonged reaction time.

Scheme 2 Scope of quinone and boronic acid coupling partners. ^aReaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), K₂S₂O₈ (2.0 equiv.), CH₂Cl₂–H₂O (1 : 1, v/v, 4 mL) at 80 °C; ^bisolated yields; ^cthe reaction was performed in the presence of Et₃N (10.0 equiv.) at 80 °C in CH₂Cl₂–H₂O (1 : 1, v/v, 4 mL).

As a part of the study we next examined the reactivity of 1,4 naphthoquinone (4a) and its derivatives. In the case of 1,4 naphthoquinone (4a), the desired product 5a could not be obtained under the optimum reaction conditions, however in the presence of triethylamine (TEA, 10.0 equiv.) the expected product 5a was obtained albeit in low yield (14%). In the presence of diisopropylamine the product 5a was formed only in 5% yield, whereas in the presence of inorganic bases such as K₂CO₃ and NaOH the yield was decreased to a trace. Similarly, 4-methoxyphenylboronic acid (2b) and 3-methoxy phenylboronic acid (2l) furnished the expected products 5b and 5c in 14% and 11% respectively. Interestingly, the hydroxyl group in 2-hydroxy naphthoquinone (4b) tolerated the reaction conditions well and the arylated quinone 5d was obtained in moderate yield (45%).

In the absence of TEA, while 2-methoxy naphthoquinone (4c) failed to undergo reaction with phenylboronic acid (2a, Scheme 3, eqn (1), 5e), it underwent reaction with 4-methoxy boronic acid (2b, Scheme 3, eqn (1)) successfully albeit in low yield 5f. Surprisingly, in the presence of TEA, the –OMe, –OCOCH₃ and –OCOPh naphthoquinones 4c–e underwent a C–O bond cleavage reaction to give the corresponding arylated naphthoquinones 5a and 5d in low yields (eqn (3)–(5), Scheme 3). It is interesting to note that in the absence of Et₃N no C–O bond cleavage took place indicating that a base plays a vital role in C–O bond cleavage (eqn (1) and (2), Scheme 3). To the best of our knowledge, it is for the first time that C–O bond cleavage of naphthoquinone derivatives such as 4c, 4d, and 4e was observed in the presence of K₂S₂O₈ and TEA.

Scheme 3 K₂S₂O₈–Et₃N mediated C–O bond cleavage of naphthoquinones.

With these impressive results, we further focused on application of the same oxidant system for arylation of different heterocycles such as pyridine (6a), 4-acetyl pyridine (6b), quinoline (6c) and bipyridine (6d) (Scheme 4). Among the different heterocycles, quinoline (6c) was successful in undergoing reaction with the aryl radical to give 7c in moderate yield. While bipyridine (6d) produced a low yield of the product 7d, pyridine (6a) and 4-acetyl pyridine (6b) produced only a trace amount of the products 7a and 7b. Further attempts to enhance the yield for the formation of expected products 7a and 7b were not successful. This may be due to the salt formation of the pyridinium ring system during the course of the reaction.

Scheme 4 Scope of heterocycles and boronic acid coupling. ^aReaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), K₂S₂O₈ (2.0 equiv.), CH₂Cl₂–H₂O (1 : 1, v/v, 4 mL) at 80 °C. ^bIsolated yields.

To demonstrate the synthetic utility of the present method, a gram-scale experiment was carried out, under the optimal reaction conditions, on benzoquinone (1a, 3.0 g) using phenylboronic acid (2a, Scheme 5). The arylated product 3aa was obtained in 61% isolated yield (3.1 g), which shows that the present method can be easily adopted for the large scale preparations.

Scheme 5 Gram-scale synthesis of aryl benzoquinone.

To study the reaction mechanism, a radical scavenger effect was investigated by adding TEMPO in the reaction between benzoquinone (1a) and phenylboronic acid (2a). Obviously, the yield decreased from 72% to 12% when 2.0 equiv. of TEMPO was added. This result shows that the reaction takes place through a radical mechanism and complies with the reported literature.¹⁰ Based on these results, a suitable mechanism is proposed (Scheme 6). Initially, K₂S₂O₈ thermally decomposes to form a sulfate radical (SO₄⁻˙),^13a,b which in turn reacts with arylboronic acid 2a to give an aryl radical A.^13c,14 Further, aryl radical A reacts with quinone 1a to give B, which on re-oxidation afforded the desired product 3a (Scheme 6).

Scheme 6 A plausible reaction mechanism.

Conclusion

In summary, the present study shows that aryl radicals could be generated from arylboronic acid under metal free conditions by means of K₂S₂O₈ and used for C–H functionalization of quinones and heterocycles. The radical pathway involved in the reaction was established by studying the reaction in the presence of a radical scavenger. The present method avoids metals and ligands. K₂S₂O₈ is inexpensive, environmentally benign, and found to show high efficiency to generate radicals at high temperature. This method is simple, scalable, and does not require any pre-functionalization of quinones. Further study on applications of this reaction is underway in our laboratory.

Acknowledgements

AP and GS thank UGC, New Delhi, for the award of BSR-RFSMS and senior research fellowship respectively. We thank DST-FIST for the use of instrument facility at the School of Chemistry, Bharathidasan University.

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Footnote

† Electronic supplementary information (ESI) available: Experimental, spectral data and copies of spectra. See DOI: 10.1039/c5qo00246j

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