Palladium-catalysed methylation of aryl halides in ionic liquids with stabilized AlMe3

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Abstract

A new protocol for the methylation of aryl halides using the AlMe3 analogue DABAL-Me3 in a VOC/IL biphasic system is described. Very good isolated yields and chemoselectivities (methylation vs homocoupling), were observed in alkylmethylimidazolium and DABCO-based ILs, in presence of a bulky substituted phosphine (XPhos) and the structurally related sulfonated phosphine (XPhosSO3H). Recycling experiments of the IL-catalyst systems were satisfactory only in case of the butyldimethylimidazolium IL due to catalyst loss to the VOC phase.

Graphical abstract

Methylation of aryl halides with DABAL-Me3 in a VOC/IL system is proposed. Good yields and high chemoselectivity were observed. Satisfactory recycling of catalytic phase was attained using a charged phosphine ligand.

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Introduction

Trialkylalanes (such as AlMe3 and AlEt3) are potentially very useful sources of alkyl anions in organic synthesis. However, their practical use is limited, due to their pyrophoric nature and the tendency to act as Lewis acids rather than as nucleophiles. In recent years, several stabilized adducts derived from trialkylaluminum have been synthesised, mainly by Schumann [1], Blum [2] and their co-workers. However, these reagents are still significantly air- and moisture-sensitive necessitating their handling under inert atmospheres. Despite this limitation they have been used, with some degree of success, in palladium-catalyzed methylation of sp2 halides [2]. Very recently a known air-stable organoaluminum adduct bis(trimethylaluminum)-1,4-diazobicyclo[2.2.2]octane adduct (DABAL-Me3, see Fig. 1) [3], [4] was reported to be active in some methylation reactions, including some asymmetric examples [5], [6]. This DABAL-Me3 reagent is technically attractive as it can be conveniently weighed out in air.

As DABAL-Me3 had been reported to be active in Pd-catalyzed methylation of aryl and vinyl halides and triflates [7] we were interested in seeing if this reaction could be carried out in small amounts of ILs-offering the prospect of catalyst recycling through the use of biphasic catalysis. In recent years several ionic liquids (such as those based on pyridinium, imidazolium, ammonium, phosphonium cations with a variety of anions) have been extensively used in transition-metal-catalysed processes [8], [9], [10], [11]. The peculiar physico-chemical properties of ionic liquids (ILs) including: negligible vapour pressure, thermal stability, selective immiscibility and wide liquid range can be tuned for specific applications simply by changing the anion and/or the cation facilitating biphasic catalysis. For transition-metal-catalysed reactions, ILs can present several advantages over molecular solvents including: enhanced reaction selectivity, possible stabilisation of the catalyst, finally potential recycling of the catalytic phase by extraction of the product using a suitable biphasic system [8], [9], [10], [11]. In this respect, as most ionic liquids are not completely miscible with VOCs (Volatile Organic Compounds), they are excellent candidates for biphasic catalysis. ILs can be efficiently used to immobilise noble-metal-containing catalysts, usually by adding charged ligands, thus minimising the amount of IL employed in the reaction [11]. Such approaches are needed for commercial applications of relatively expensive ILs [12].

Herein we report the use of ILs in palladium-catalysed methylation of aryl halides with the convenient methylating agent DABAL-Me3. It was anticipated that the results would compare well with those obtained in molecular solvents [7], but also demonstrate the possible reuse of a catalytic IL phase operated under biphasic conditions with traditional organic solvent.

Section snippets

Materials

Substrates and ligands were purchased from Sigma–Aldrich, Alfa Aesar, Lancaster, Merck and used without further purification. DABAL-Me3 was purchased from Sigma–Aldrich and stored under inert atmosphere (Ar). Sulfuric acid (84% w/w) was purchased from Pharmacos and oleum from Sigma–Aldrich.

Solvents were purchased from Fluka, Lancaster and Carlo Erba and were either of anhydrous grade or dried according to literature procedures [13].

The pre-catalyst Pd2(dba)3 was purchased from Sigma–Aldrich and

Results and discussion

Methylation reactions of aryl halides have been performed using DABAL-Me3 in the presence of Pd(0) or Pd(II) catalysts precursors under biphasic conditions. Several parameters, such as the nature of the IL, the Pd source, the ligand, and time/temperature of the reaction optimised. Initially, two alkylmethylimidazolium-based ILs were tested: the hydrophobic 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide ([C4mim]Tf2N) and the hydrophilic 1-butyl-3-methylimidazolium

Conclusions

A new protocol for the methylation of aryl halides with DABAL-Me3 in a IL/VOC two-phase system was optimised and tested on a number of substrates, giving positive results. Reactions were performed in classic alkylmethylimidazolium IL and a DABCO-based IL, in the presence of a bulky substituted phosphine (XPhos) and a structurally similar charged phosphine (XPhosSO3H). In all cases satisfactory results were obtained in terms of isolated yields and chemoselectivity (methylation vs homocoupling).

A

Acknowledgements

COST D40 Action framework is gratefully acknowledged for promoting the interaction between the two research groups. SW thanks the Engineering and Physical Research Council (EPSRC) for support through grant EP/F033478/1. Experimental contribution by Mr. Fabio Querini on [C6DABCO] BF4 is acknowledged. Thanks are due to Profs. Peter Licence and Stefan Toma for providing a sample of [C4mmim]BF4 and of FcPhos, respectively and to Prof. Fausto Calderazzo for helpful discussion.

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