PTS: Powerful Amphiphile for Organic Reactions in Water

By: Dr. Mark Redlich, Chemfiles Volume 10 Article 1

        Dr. Mark Redlich

Dr. Mark Redlich
Product Manager
Email:mark.redlich@sial.com

Polyoxyethanyl a-tocopheryl sebacate, PTS, is a nonionic amphiphile recently introduced by Professor Bruce Lipshutz of UC-Santa Barbara that is proving to be a versatile "solubilizer" for organic molecules in water.1 Lipophilic substrates and catalysts can efficiently enter the 25-nm micelles formed by PTS in water leading to important cross-coupling reactions such as metathesis,2 Suzuki–Miyaura,3 Heck,4 and Sonogashira reactions5 at room temperature. Importantly, there is no need for a co-solvent to enhance water solubility of lipophilic substrates in these reactions. One simply places the requisite amount of PTS (15 wt % in water) into a test tube with a stir bar and adds the organic substrate(s) and catalyst. Reactions are generally complete within 3–24 hours and can be accelerated if needed upon mild heating to 40–50 °C. Work-up is also very simple, involving either extraction of the reaction mixture with EtOAc-hexane or deposition onto a bed of silica gel and elution with EtOAc.

In the past couple of years, Lipshutz and co-workers have been rapidly expanding the range of successful applications of micellar catalysis using PTS in water. Palladium-catalyzed allylic aminations of allylic alcohols proceed smoothly in water giving good to excellent yields with good selectivity. The allylic amination was applied to a one-pot synthesis of the antifungal agent naftifine at room temperature, which previously was accessible only through multi-step or high temperature processes (Scheme 1).6

Scheme 1

Scheme 1


Functionalized allylic ethers were also found to be reliable substrates for Suzuki–Miyaura coupling using PTS in water at ambient temperatures (Scheme 2).3c Catalyst loadings could be reduced as low as 0.5 mol % in some cases when the reaction is gently heated to 40 °C.

Scheme 2

Scheme 2


An alternative to Negishi-type coupling was also reported by Lipshutz wherein palladium-catalyzed, zinc-mediated C–C bond forming occurs without requiring a preformed organometallic coupling partner (i.e., RZnI). Primary alkyl iodides react readily with aryl bromides in the presence of fresh zinc powder, a palladium catalyst and TMEDA in 2 wt % PTS in water to generate the adduct in good to very good yields (Scheme 3).7

Scheme 3

Scheme 3


The micellar catalysis methodology has recently been extended to the synthesis of allylic silanes from allylic ethers and readily available disilanes.8 The couplings are very efficient, and occur with well-controlled selectivity. The mildness of the reaction conditions in PTS-H2O media allowed for a one-pot chemoselective amination/silylation sequence to provide a dibenzylated methallylsilane in good yield, without the need for any organic solvent (Scheme 4).

Scheme 4

Scheme 4


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Materials

     

References

  1. Sold under license from Zymes, LLC.
  2. a) Lipshutz, B. H. et al. Org. Lett. 2008, 10, 1325. b) Lipshutz, B. H. et al. Adv. Synth. Catal. 2008, 350, 953.
  3. a)Lipshutz, B. H. et al. Org. Lett. 2008, 10, 1333. b) Lipshutz, B. H.; Abela, A. R. Org. Lett. 2008, 10, 5329. c) Nishikata, T.; Lipshutz, B. H. J. Am. Chem. Soc. 2009, 131, 12103.
  4. a)Lipshutz, B. H.; Taft, B. R. Org. Lett. 2008, 10, 1329. b) Lipshutz, B. H.; Ghorai, S. Aldrichimica Acta, 41, 59.
  5. Lipshutz, B. H. et al. Org. Lett. 2008, 10, 3793.
  6. Lipshutz, B. H.; Nishikata, T. Org. Lett. 2009, 11, 2377.
  7. Krasovskiy, A. et al. J. Am. Chem. Soc. 2009, 131, 15592.
  8. Moser, R. et al. Org. Lett. 2009, 11, ASAP.

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