AmmoniaAmmonia--FreeFree Birch Reductions Using Stabilized Sodium In nn--SilicaSilica for Safer, More Sustainable Synthesis Michael J. Costanzo, Mitul N. Patel, Kathryn A. Petersen, and Paul F. Vogt June 2009 About SiGNa Chemistry A chemical technology company with a growing portfolio of “GREEN” products and processes for improved efficiency and a cleaner environment Alternative Energy: • Clean H2 from water for a bdbroad range of idindus tiltrial process and portbltable flfuel cell applications Green Industrial Processes: • Improved industrial efficiency and yield with critical cost reduction using green chemical processing Clean Technology: • Cleaner burning conventional petroleum‐ and bio‐based fuels • Remediation of hazardous environmental contaminants SiGNa Technology Overview SiGNa’s Scientific Council H2 Fuel Technology H2 gas produced from water Room‐temp. operation, no catalyst Near instant start‐stop functionality NNon‐titoxic by‐proddtucts JL Dye Sir JM Thomas RH Grubbs GD Stucky Products: Reagents (NaSi) and fuel systems Knighted in 2005 Nobel Prize 1991 Chemistry Applications: Fuel cells and industrial H2 “Green” Catalysts Low cost and scalable Renewable starting materials Environmentally‐friendly operation Non‐toxic by‐products Products: EP Catalyst and AlPOs Applications: EPDM rubber and ethylene Specialty Chemicals Stable in dry air / safe to handle Retains chemical power of base alkali metal Free‐flowing conductive powder Non‐toxic by‐products Products: M‐SG, OrganoLi‐AG, and MH‐SG Applications: Chemical manufacturing, desulfurization, and remediation (PCBs) Applications of SiGNa Materials Desulfurization Chemical Reductions Dissolving Metal Reductions Fuel Cells and Hydrogen Alternative Energy Generation LAH Palladium Replacement Replacement Olefin Isomerization Solvent Drying and Purification PCB/CFC Remediation and Deuterium and Radio‐label Freon Conversion Carbon‐Carbon Incorporation Bond forming Reactions Alkali Metals React with Water Overview of SiGNa’s Technology Metals solvated in nano‐structured porous oxides Alkali metal silica materials (M‐SG); capacity up to 40 wt.% Stable in dry air / Safer to handle / easier to transport Free‐flowing powders Reducing power of the parent metal/alloy retained Non‐toxic by‐products and waste streams SiGNa’s Commercial Pipeline CONCEPT FEASIBILITY VALIDATION LAUNCH Stage I M‐SG Chemicals M+H‐‐SG OrganoLi‐AG Stage II M‐SG M+H‐‐SG Alt. Fuels NaSi Fuel System Catalysts Bio‐Zeolites AlPOs EP Catalyst The Birch Reduction Birch, A. J. J. Chem. Soc. 1944, 430. Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1. •Alternative to hydrogenation that yields cyclohexadienes. • Carried out in liquid ammonia with dissolved Na, Li or K. •Metal cation and a solvated electron are formed. •Mixture contains stoichiometric amounts of an alcohol Problems include: • Handling of alkali metal and ammonia gas • CiCryogenic temperatures •Special design of the equipment •Choice and handling of materials • Operations, waste treatment, and both safety and economic issues The Classical Birch Reduction Typical Reaction Conditions: • Phenanthrene was dissolved in THF •Solution was added to refluxing ammonia at ‐33 oC • Lithium metal (3. 5 equivalents) was added to the mixture •Reaction quenched with ethanol then water then warmed to rt • Desired product is isolated in 57% yield “Lithium wire was wiped free of oil and washed with hexane immediately before use…….” The SiGNa Birch Reduction SiGNa’s Reaction Conditions: • Phenanthrene and Na‐SG(I) (3.5 equivalents) are charged to a round bottom flask • THF is adde d and the mitixture is cooldled to 0 oC • tert‐Butanol (1.75 equivalents) is added in one portion •Reaction is allowed to warm to room temperature • DidDesired product is ilisolate d in 60% yildield NO LIQUID AMMONIA! NO CRYOGENIC TEMPERATURES! NO PYROPHORIC REAGENTS! MM--SGSG Reaction Parameters Temp. (°C) Prod. (%) -78 90 Similar conversions were observed with: 0 81 2.0 to 7.5 equivalents of metal Stage I with Na, Na2KandK2Na 22 82 t‐butanol and t‐amyl alcohol 40 87 reflux 81 MM--SGSG Solvent Compatibility Solvent Prod. (()%) Solvent Prod. (()%) THF 81 Cyclohexane 83 Me-THF 85 Heptane 82 Dioxane 76 DME 67 MTBE 75 EtOAc 0 DMSO 3 NMP 19 Toluene 84 t-Amyl-OH (neat) 2 Polycyclic Aromatic Hydrocarbons SiGNa’s safer and more practical modification of the classic Birch reduction that avoids the use of liquid ammonia and cryogenic temperatures Na-SG(I) Na/NH (lit.) Entry Substrate Major Product Rxn Equiv. Time (h) 3 Prod./Yield (%) Prod./Yield (%) 1 353.5 202.0 96 / 70 --/85/ 85 2 2.0 1.0 87 / 83 - - / 97 3 353.5 252.5 99 / 94 --/96/ 96 Aromatic Hydrocarbons Na-SG(I) Na/NH (lit.) Entry Substrate Major Product Rxn Equiv Time (h) 3 Prod./Yield (()%) Prod./Yield (()%) 1 3.5 2.0 100 / 83 - - / 80-90 2 353.5 202.0 100 / 82 --/80/ 80-90 3 14 24 9 / - - - - / 63 Aryl Ethers Na-SG(I) Na/NH (lit.) Entry Substrate Major Product Rxn Equiv Time (h) 3 Prod./Yield (%) Prod./Yield (%) 1 14 24 30 / - - - - / 74 OMe 2 353.5 24 12 / - - - - /19/ 19 OMe 3 3.5 24 68 / 43 - - / - - 4 14 24 85 / 68 --/74/ 74 5 5.6 24 - - / 56 --/ -- 6 3.5 2.5 92 / 80 - - / 74 (liq. NH3) Polycyclic Aromatic Heterocycles Na-SG(I) Na/NH (lit.) Entry Substrate Major Product Rxn Equiv Time (h) 3 Prod./Yield (%) Prod./Yield (%) Et 1 565.6 24 --/ 58 --/ 69 OH 2 14 48 94 / 62 - - / 15 3 3.5 2.0 89 / 38 - - / - - 4 3.5 2.0 77 / 40 - - / 89 Case Study – Birch Reduction Goal: Develop a manufacturing process for a Birch reduction of a steroid that does not require liquid ammonia and cryogenic temperatures Results: Conditions were developed which used SiGNa materials in THF at 0 °C without the use of liquid ammonia. Minimized the amount undesired side-products and comparable yields and purities were observed. Eliminated the expensive part of the client’s regular Birch reduction which was the required cooling capacity of the reaction and ammonia recycle. Lowered the client cost of goods by 18% – allowed th em access t o a new prod uct li ne Birch with Deuterium Incorporation SiGNa’s Reaction Conditions: • Phenanthrene and Na‐SG(I) (3.5 equivalents) are charged to a round bottom flask and stirred • THF is added and the mixture is cooled •Reaction is allowed to warm to room temperature and quenched with D2O • Desired product is isolated in similar yields and purities •NMR integrations shows deuterium incorporation product in 81% yield When performing a reduction with SiGNa materials, any C‐H bond formed can be also be converted into a C‐D bond SiGNa’s Competitive Advantage Sodium Metal (Na0) in Water: SiGNa Na‐SG in Water: SiGNa’s alkali metals solvated in nano‐structured porous oxides: Significantly simplifies processes while mitigating risks Generates non‐toxic by‐products and waste streams Potential to Save $MMs for Each Process!! SiGNa Deprotections Deallylation Debenzylation Desulfonation Nandi, P.; Redko, M. Y.; Petersen, K.; Dye, J. L.; Lefffenfeld, M.; Vogt, P. F.; Jackson, J. E. Organic Letters 2008, 10 (23), 5441. Case Study – Palladium Contamination Goal: Develop a deprotection step which minimized palladium in the API and that does not require a resin treatment or other precious metal removal step Results: Desired deprotection was achieved using SiGNa materials to give target API in comparable yields and purities to Pd/C hydrogenolysis route. Palladium content of API, inherently, was 0 ppm. No extra work up steps or purifications were required. New route removed regulatory hurdle to filling New Drug Application. Lowered the client’s cost of goods by 24% – Increased productivity by 50% Order SiGNa Materials Today Prod. No. Product Name Size 44893 Stage I Sodium-Silica Gel 5g, 25g, 100g 44894 Stage II Sodium-Silica Gel 5g, 25g, 100g www.alfa.com 44892 Stage I Na2K-Silica Gel 5g, 25g, 100g 44890 Sta ge I K2Na-Silica Ge l 5g, 25g, 100g Prod. No. Product Name Size 660167 Stage I Sodium-Silica Gel 5g, 25g, 100g 660175 Stage II Sodium-Silica Gel 5g, 25g, 100g 660159 Stage I Na2K-Silica Gel 5g, 25g, 100g www.sigmaaldrich.com 660140 Stage I K2Na-Silica Gel 5g, 25g, 100g To purchase development and commercial volumes of SiGNa materials or for technical support, please contact SiGNa Chemistry directly at [email protected].