Cross-Couplings in Water
Conducting transition metal-catalyzed cross-coupling chemistry in water instead of organic solvent has a number of potential benefits in terms of cost, environmental impact, safety, and impurity profiles. Increasing focus on the “green-ness” of chemical processes has further promoted recent development in this field. The actual means of implementing reactions in water, however, especially at room temperature and for water insoluble organic substrates, has not always been clear. One solution that has been applied to a broad range of transition-metal-catalyzed processes is the use of small amounts of a nanomicelle-forming amphiphile in water which provides a lipophilic medium where cross-coupling reactions can take place.
Beginning in 2008, Lipshutz et al. have published a series of papers demonstrating the viability of surfactant promoted, transition metal-catalyzed chemistry in water at room temperature. Using a variety of commercially available surfactants, a number of palladium- and ruthenium-catalyzed processes were found to be amenable to mild, room temperature reactions in water. Products can be recovered from the aqueous phase using standard extraction procedures and in high isolated yields
TPGS-750-M: A Second Generation Amphiphile
Lipshutz and co-workers have recently developed a second generation technology to their original PTS-enabling surfactant based on the polyoxyethanyl-α-tocopheryl succinate derivative, TPGS-750-M (Figure 1). This designer surfactant is composed of a lipophilic α-tocopherol moiety and a hydrophilic PEG-750-M chain, joined by an inexpensive succinic acid linker, spontaneously forms micelles upon dissolution in water. The balance and composition of TPGS-750-M’s lipophilic and hydrophilic components has been tailored to promote a broader array of chemistry in water more efficiently than that seen in PTS. Furthermore, this new, more practical surfactant can be readily be substituted for older amphiphiles, usually with equal or greater efficiency in terms of both yield and reaction times.
Employing the second generation Grubbs catalyst (2 mol %) a variety of lypophillic substrates successfully undergo ring-closing or cross-metathesis in water at room temperature to produce high isolated yields of the desired products (Scheme 2). Reactions were conducted in 2.5% TPGS-750-M/water, with yields equal to or slightly better than those performed using various other surfactant-water combinations.
Pd-Catalyzed Cross Coupling Reactions
A variety of widely used palladium-catalyzed cross-coupling reactions can now be run under mild room temperature conditions in water with TPGS-750-M, using a variety of commercially available palladium complexes and ligands. These transformations, including Heck, Suzuki-Miyaura, Sonogashira, and Buchwald-Hartwig aminations, are amongst the most heavily used bond forming reactions, both industrially and academically (Scheme 3).
Similar, operationally extremely simple Suzuki-Miyaura reaction using micellar catalysis and bis(di-tert-butylphosphino)ferocene palladium chloride complex provides access to highly sterically congested substrates at room temperature using triethylamine as the base.
Sonogashira reaction and Buchwald-Hartwig aminations are also amenable to reaction in water with TPGS-750-M using the palladium chloride/X-Phos combination in the former, and allyl palladium chloride/cBRIDP in the latter (Scheme 4).
Heck cross-couplings with aryl iodides can be successfully performed using Pd(P(t-Bu)3)2 as the palladium source in the bulk aqueous environment containing TPGS-750-M (5 wt. %) obviating the need for high temperatures commonly associated with Heck reactions.
Zinc-mediated Negishi-like couplings between aryl and alkyl halides can be performed in aqueous TPGS-750-M (Scheme 5). Under these conditions, typically highly moisture sensitive organozinc halides, are formed in situ from an alkyl halide and zinc dust, and react with an aryl halide under palladium catalysis. With the aid of a surfactant and a stabilizing ligand for RZnX, such as tetramethylethylenediamine (TMEDA), this entire process takes place in water, leading to a variety of primary and secondary alkyl-substituted aromatics. The choice of catalyst is crucial for the success of the reaction; Pd(Amphos)Cl2 was found to be the optimal catalyst..
C-H Activation Reactions
Cationic palladium in combination with stoichiometric oxidant benzoquinone and silver nitrate successfully catalyzes ortho functionalization of a variety of aryl acetamides in water at room temperature using this amphiphile (Scheme 6).