A new paradigm for Pd-catalyzed cross-couplings between alkyl and aryl halides in water at room temperature will be further developed. Reactive, highly water-sensitive sp3-based organozinc reagents can be generated in situ and used as coupling partners, protected from their aqueous surroundings by a micellar environment. A study on the use of alkyl bromides as a less costly alternative to iodides will be undertaken. This new micellar nanotechnology will be applied to related cross-couplings of stereo-defined alkenyl halides. Such couplings would be an especially attractive alternative to Suzuki-Miyaura couplings that normally require prior formation of boronic acids or the equivalent. The stereochemistry of the products resulting from these couplings in water relative to that seen in organic solvents will also be compared. Related couplings applied to heteroaromatic halides will be studied, given the importance of heterocycles to the pharmaceutical industry. Novel transition metal-catalyzed tandem processes will be developed, both reactions of in this sequence to be conducted in water at room temperature. Stille couplings involving organostannane intermediates will also be investigated as coupling partners in micellar media. The first cases of couplings using nickel catalysis will also be further investigated in reactions of alkenyl halides with in situ-generated organozinc halides. A newly designed, inexpensive yet "healthy" surfactant has been identified and will be developed that enables room temperature couplings for several name reactions to be done in water. Higher levels of conversion relative to those seen in previous studies can be achieved, and hence, better yields of cross-coupling products are to be expected. The secret to this success is based on proper engineering of particle size, which better accommodates the intended chemistry.

Public Health Relevance

New technologies are to be developed that get organic solvents out of organic reactions;that replace traditional processes that use strictly organic media with a green alternative: water. These studies are driven by the potential for decreasing the amount of solvent waste, to be carried out by investigating several reactions in water that are important to the pharmaceutical and fine chemicals areas. All are to be done at room temperature, and thus, without any investment of energy for either heating or cooling purposes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Lees, Robert G
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University of California Santa Barbara
Schools of Arts and Sciences
Santa Barbara
United States
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Klumphu, Piyatida; Lipshutz, Bruce H (2014) "Nok": a phytosterol-based amphiphile enabling transition-metal-catalyzed couplings in water at room temperature. J Org Chem 79:888-900
Handa, Sachin; Lippincott, Daniel J; Aue, Donald H et al. (2014) Asymmetric gold-catalyzed lactonizations in water at room temperature. Angew Chem Int Ed Engl 53:10658-62
Kelly, Sean M; Lipshutz, Bruce H (2014) Chemoselective reductions of nitroaromatics in water at room temperature. Org Lett 16:98-101
Krasovskiy, Arkady L; Haley, Stephen; Voigtritter, Karl et al. (2014) Stereoretentive Pd-catalyzed Kumada-Corriu couplings of alkenyl halides at room temperature. Org Lett 16:4066-9
Lipshutz, Bruce H; Ghorai, Subir (2014) Transitioning organic synthesis from organic solvents to water. What's your E Factor? Green Chem 16:3660-3679
Isley, Nicholas A; Dobarco, Sebastian; Lipshutz, Bruce H (2014) Installation of protected ammonia equivalents onto aromatic & heteroaromatic rings in water enabled by micellar catalysis. Green Chem 16:1480-1488
Fennewald, James C; Lipshutz, Bruce H (2014) Trifluoromethylation of Heterocycles in Water at Room Temperature. Green Chem 16:1097-1100
Handa, Sachin; Fennewald, James C; Lipshutz, Bruce H (2014) Aerobic oxidation in nanomicelles of aryl alkynes, in water at room temperature. Angew Chem Int Ed Engl 53:3432-5
Minkler, Stefan R K; Isley, Nicholas A; Lippincott, Daniel J et al. (2014) Leveraging the micellar effect: gold-catalyzed dehydrative cyclizations in water at room temperature. Org Lett 16:724-6
Lipshutz, Bruce H; Boskovic, Zarko; Crowe, Christopher S et al. (2013) "Click" and Olefin Metathesis Chemistry in Water at Room Temperature Enabled by Biodegradable Micelles. J Chem Educ 90:

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