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24 Cross-Couplings in Water Conducting transition metal-catalyzed cross-coupling chemistry in water instead of organic solvent has a number of potential benefi ts in terms of cost, environmental impact, safety, and impurity profi les. Increasing focus on the “green-ness” of chemical processes has further promoted recent developments in this fi eld. 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 in which cross-coupling reactions can take place. Micellar Catalysis Aldrich.com Synthetic Reagents Troy Ryba, Ph.D. Product Manager troy.ryba@sial.com TPGS–750–M: Second Generation Amphiphile for Organometallic Chemistry in Water @ RT Beginning in 2008, Lipshutz et al. 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 TO ORDER: Contact your local Sigma-Aldrich offi ce (see back cover), or visit Aldrich.com/chemicalsynthesis. Lipshutz and co-workers have recently developed a second generation technology to their original PTS-enabling surfactant based on a polyoxyethanyl-α-tocopheryl succinate derivative, TPGS-750-M (733857) (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, and 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 effi ciently than that seen in PTS. Furthermore, this new, more practical surfactant can be readily substituted for older amphiphiles, usually with equal or greater effi ciency in terms of both yield and reaction times. Figure 1: TPGS–750–M. 3 O O O O O O O Me 16 *Special thanks to Professor Bruce Lipshutz, Zarko V. Boskovic and Alex R. Abela of University of California, Santa Barbara for contributing this article on TPGS-750-M.
Olefi n Metathesis 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 1). 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. OTBS N Ts Scheme 1: Selected olefi n metathesis. O O Grubbs-2 (2 mol %) 2.5% TPGS-750-M, water 22 o C, 12 h Grubbs-2 (2 mol %) 2.5% TPGS-750-M, water 22 o C, 12 h O OTBS 91% N Ts 88% 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 Suzuki-Miyaura, Sonogashira, Buchwald-Hartwig aminations, and Heck, are amongst the most heavily used bond forming reactions, both industrially and academically (Scheme 2). I Br Br + + B(OH) 2 OMe Br NH 2 + OMe + 2 mol % Pd(dtbpf)Cl2 Et3N (3 equiv) 2% TPGS-750-M, water 20 °C, 24 h 3% TPGS-750-M, water 22 o PdCl2(CH3CN)2 (1 mol %) X-Phos (2.5 mol %) Et3N (2 eq.) C, 21 h [(allyl)PdCl] 2 (0.5 mol %) Takasago's cBRIDP (2 mol %) KOH (1.5 equiv) 2% TPGS-750-M, water 22 o C, 19 h (PtBu3)2Pd (2 mol %) Et3N (3 equiv) 5% TPGS-750-M, water 22 o C, 12 h Scheme 2: Selected Pd-catalyzed cross coupling reactions. Operationally extremely simple Suzuki-Miyaura reactions using micellar catalysis and bis(di-tert-butylphosphino)ferrocene palladium chloride complex provide access to highly sterically congested substrates at room temperature using triethylamine as base. O 88% 99% H N 93% Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich offi ce, or visit safcglobal.com. OMe 95% OMe Synthetic Reagents Sonogashira reactions 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 (Figure 2). Figure 2: Selected ligand examples. 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 3). 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)2Cl2 (Bis(di-tert-butyl (4-dimethylaminophenyl)phosphine) palladium(II) chloride) was found to be the optimal catalyst. Scheme 3: Selected Negishi-like cross-coupling example. 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 4). Scheme 4: Selected C–H activation reaction. H OMe Br H N O i-Pr + EtO2C + i-Pr PCy2 i-Pr Reference: Lipshutz, B. H.; Ghorai, S. Aldrichimica Acta 2008, 41, 59. For more information on TPGS–750–M, visit Aldrich.com/tpgs750m Ph Ph Me X-Phos cBRIDP 638064 O Br On-Bu P(t-Bu)2 685151 0.5% Pd(Amphos)2Cl2 TMEDA (1 equiv) Zn dust (3 equiv) 2% TPGS-750-M, water, rt EtO2C [Pd(MeCN)4](BF4)2 (10 mol %) BQ, AgNO3 2% TPGS-750-M, water, rt OMe 80% CO2n-Bu H N 83% O 25
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Page 23: Thiazoles Thiazoles have been frequ
Page 27 and 28: Unlock a smarter, greener laborator
Page 29 and 30: Specialty NMR Solvents Aldrich off
Page 31 and 32: Eliminating Static from Glove Boxes

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