A practical protocol for the synthesis of bibenzyls via C(sp³)–H activation of methyl arenes under metal-free conditions

Abstract

A variety of bibenzyl derivatives have been synthesized with excellent atom economy via C(sp³)–H–C(sp³)–H coupling of readily available methyl arenes using K₂S₂O₈ under metal-free and environmentally benign conditions.

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Introduction

Transition metal-catalyzed C–C bond formation is one of the most important transformations in organic synthesis.¹ During the past few years, C–H activation reactions have attracted a great deal of attention for the preparation of valuable compounds.² Most recently, the versatility of transition metal catalysts has allowed the discovery of a variety of new strategies in activating both C_sp²–H and C_sp³–H bonds for carbon–carbon bond creation.³ Yet, only a few methods have been developed for C_sp³–HC_sp³–H bond formation because of the low reactivity of C_sp³–H bonds.⁴ The direct coupling of two C_sp³–H bonds to generate a C–C bond is quite demanding and challenging because of its high atom economy. Methyl arenes are inexpensive and abundant organic molecules, and the methods for their direct/selective functionalization are highly tempting. Although adequate attention has been paid to the C_sp³–H activation of methyl arenes,⁵ many of the reactions described so far invariably employ expensive/toxic transition metals and severely suffer from the excessive use of methyl arenes and oxidants.

The bibenzyl motif is generally found in many natural products and exhibits potential biological and agricultural activities.⁶ Some of the bibenzyl derivatives are used as starting materials for the synthesis of highly useful drug molecules.⁷ Traditional methods for the synthesis of bibenzyls involve reduction of stilbene/diphenylacetylene derivatives.⁸ In recent times, bibenzyl derivatives have been synthesized by using homocoupling of benzyl halides,⁹ benzylmagnesium halides,¹⁰ and phenylacetic acids¹¹ (Scheme 1). However, these methods require pre-functionalization of the starting materials as well as the use of expensive transition metal catalysts. Therefore, a metal-free and mild protocol for the synthesis of bibenzyl derivatives employing economical and readily available starting materials is highly demanding.

Scheme 1 Previous and present reports.

In view of the above and as a part of our ongoing interest in developing new protocols involving C–H activation,¹² and others,¹³ we disclose herein an efficient K₂S₂O₈ mediated homocoupling of methyl arenes for the synthesis of bibenzyl derivatives under metal-free conditions (Scheme 1).

Results and discussion

In order to optimize the reaction conditions, a model reaction employing p-xylene as a substrate was thoroughly investigated by varying different parameters such as the catalyst, oxidant, solvent(s) and temperature, and the outcome is given in Table 1.

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst (mol %)	Oxidant	Solvent/solvents (1 : 1)	Temp (°C)	Yield^b (%)
a Reaction conditions: 1b (1.0 mmol), catalyst (20 mol%), oxidant (2.0 mmol), solvent (2 ml), 10 h. b Isolated yield.
1	AgNO3 (20)	K2S2O8	CH3CN/H2O	60	56
2	AgNO3 (20)	K2S2O8	CH3CN/H2O	70	68
3	AgNO3 (20)	K2S2O8	CH3CN/H2O	80	75
4	AgNO3 (20)	K2S2O8	CH3CN/H2O	90	73
5	—	K2S2O8	CH3CN/H2O	80	76
6	—	K2S2O8	DCE/H2O	80	0
7	—	K2S2O8	DMSO/H2O	80	0
8	—	K2S2O8	DMF/H2O	80	0
9	—	K2S2O8	DMA/H2O	80	0
10	—	K2S2O8	NMP/H2O	80	0
11	—	Na2S2O8	CH3CN/H2O	80	68
12	—	(NH4)2S2O8	CH3CN/H2O	80	61
13	—	TBHP	CH3CN/H2O	80	0
14	—	DTBP	CH3CN/H2O	80	0
15		(NH4)2Ce(NO3)6	CH3CN/H2O	80	0
16		K2S2O8	CH3CN	80	0
17		K2S2O8	H2O	80	0

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To our outmost delight, when the reaction was conducted using AgNO₃ (20 mol%) as the catalyst and K₂S₂O₈ (2 equiv.) as the oxidant in CH₃CN/H₂O (1 : 1) at 60 °C for 10 hours, the homocoupled product 1,2-di-p-tolylethane (2b) was formed in 56% yield (Table 1, entry 1). Increasing the reaction temperature to 70 °C and 80 °C increased the product yields to 68% and 75% respectively (entries 2 & 3). Further increase in the temperature to 90 °C, however, did not improve the product yield again (entry 4). Notably, when the reaction was carried out in the absence of AgNO₃ at 80 °C, the product 2b was obtained in 76% yield (entry 5). Afterwards, the effect of different solvent systems such as DCE/H₂O, DMSO/H₂O, DMF/H₂O, DMA/H₂O and NMP/H₂O was studied to improve the product yield, which remained entirely futile (entries 6–10). Switching the oxidant to Na₂S₂O₈ and (NH₄)₂S₂O₈ also did not augment the product yield (entries 11 & 12). Surprisingly the use of oxidants like TBHP, DTBP and (NH₄)₂Ce(NO₃)₆ remained completely ineffective (entries 13–15). The reaction also remained worthless, when conducted using solitary solvents like CH₃CN and H₂O (entries 16 & 17). It unequivocally reveals that the choice of the oxidant and biphasic solvent system is crucial for the success of the reaction.

With the optimized reaction conditions in hand (entry 5), the scope and limitations of the homocoupling of various methylarenes involving the C(sp³)–H bond were subsequently explored in detail (Scheme 2).

Scheme 2 The scope and versatility of the homocoupling of methylarenes. Conditions: Methylarene 1 (1.0 mmol), K₂S₂O₈ (2.0 mmol), solvents (2 ml), 10 h.

Evidently, toluene and its derivatives like m-xylene, o-xylene, p-methoxytoluene, p-chlorotoluene, m-chlorotoluene, o-chlorotoluene, p-bromotoluene, p-iodotoluene and p-fluorotoluene were readily transformed into their corresponding bibenzyls 2a–k in reasonably high yields. Dimethyl benzenes such as p-xylene, o-xylene and m-xylene surprisingly underwent dimerization involving only one methyl group to afford their corresponding bibenzyls 2b–d, with the other methyl group remaining intact. Toluene derivatives containing electron withdrawing groups such as ethyl-4-methylbenzoate, ethyl-3-methylbenzoate and ethyl-2-methylbenzoate also endured the reaction smoothly to give the desired products 2l–n in good yields. o-Substituted toluene derivatives offered lower yields compared to m- and p-substituted toluenes, perhaps due to the steric hindrance. Bicyclic methylarenes such as 1-methylnaphthalene and 2-methylnaphthalene also worked well leading to the formation of the products 2o & 2p in high yields. The results showed a wide scope and good tolerance of functional groups for the reaction, although 4-nitrotoluene and 4-methylphenol noticeably did not undergo the reaction at all under the established conditions.

Ultimately, it was thought worthwhile to extend the applicability of the reaction for cross coupling of two different methyl arenes. As a result, a representative reaction involving toluene (1a) and 1-methylnaphthalene (1o) was carried out under the established conditions by using different molar ratios of the reactants. But despite all our efforts, we could not exceed the yield of the cross coupled product 3a above 25%, which was invariably accompanied by the formation of the homocoupled products 2a and 2o (Scheme 3). A number of other cross-coupling reactions including two electronically different methyl arenes (e.g. toluene and chlorotoluene) have also been carried out under the established conditions. But we could not observe any isolable cross-coupled product. Furthermore, an intramolecular cyclization coupling using p-xylene and m-xylene was also tried by varying their molar ratios to afford a cyclophane type product, but the reaction did not proceed beyond the formation of 2b and 2c respectively, even at higher temperatures and longer reaction times. An effort was also made to cyclize the isolated products 2b and 2c under the standard conditions, but the reaction could not succeed and the starting reactants 2b and 2c remained as it is.

Scheme 3 Cross coupling reaction between 1a and 1o. Conditions: 1a (1.0 mmol), 1o (1.0 mmol), K₂S₂O₈ (4.0 mmol), solvent (4 ml), CH₃CN/H₂O (1 : 1), 80 °C, 10 h.

In order to gain an insight into the mechanistic pathway, a typical reaction as shown in Scheme 4 was carried out in the presence of a radical scavenger TEMPO, which quenched the reaction thereby revealing the involvement of a radical mechanism.

Scheme 4 Radical trapping experiment.

Based on the above observations, a plausible mechanism is outlined in Fig. 1, which is initiated with the thermal decomposition of K₂S₂O₈ to form the sulfate radical (SO₄⁻˙). The reaction of the sulfate radical with methylarene 1 gives rise to a benzyl radical, which then dimerizes to afford the bibenzyl derivatives 2.

Fig. 1 Plausible mechanism.

Conclusions

In summary, a novel and efficient K₂S₂O₈ mediated C(sp³–H) C(sp³–H) homocoupling of inexpensive methyl arenes has been developed in aqueous solution to afford bibenzyls. In addition to the broad substrate scope and functional group compatibility, the transformation is simple and metal-free. In view of its operational simplicity, easy availability of starting materials and mild reaction conditions, this method should find important applications in organic synthesis.

Acknowledgements

P. K. thanks UGC, New Delhi for the award of a DSK-Postdoctoral Fellowship with UGC Award Letter No. F.4-2/2006 (BSR)/CH/13-14/0165.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6qo00529b

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