Ammonia-Free Birch Reductions Using Stabilized Sodium In n-silica 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 H 2 from water for a broad range of industrial i process and portable fuel 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 H 2 Fuel Technology SiGNa s Scientific Council H 2 gas produced from water Room temp. operation, no catalyst Near instant start stop functionality Non toxic by products Products: Reagents (NaSi) and fuel systems Applications: Fuel cells and industrial H 2 JL Dye Sir JM Thomas Knighted in 1991 RH Grubbs 2005 Nobel Prize Chemistry GD Stucky Green Catalysts Specialty Chemicals Low cost and scalable Renewable starting materials Environmentally friendly operation Non toxic by products Products: EP Catalyst and AlPOs Applications: EPDM rubber and ethylene 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 Chemical Reductions Fuel Cells and Alternative Energy LAH Replacement Olefin Isomerization PCB/CFC Remediation and Freon Conversion Desulfurization Carbon Carbon Bond forming Reactions Dissolving Metal Reductions Hydrogen Generation Palladium Replacement Solvent Drying and Purification Deuterium and Radio label Incorporation
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 Chemicals M + H SG OrganoLi AG Stage I M SG Stage II M SG Alt. Fuels M + H SG Fuel System NaSi 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 outin liquid ammonia with dissolved Na, Li ork. Metal cation and a solvated electron are formed. Mixture contains stoichiometric amounts of an alcohol Problems include: Handling of alkali metal and ammonia gas Cryogenic 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 o C 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 added d and the mixture it is cooled ldto 0 o C tert Butanol (1.75 equivalents) is added in one portion Reaction is allowed to warm to room temperature Desired product is isolated din 60% yield ild NO LIQUID AMMONIA! NO PYROPHORIC REAGENTS! NO CRYOGENIC TEMPERATURES!
M-SG Reaction Parameters Temp. ( C) Prod. (%) -78 90 0 81 22 82 Similar conversions were observed with: 2.0 to 7.5 equivalents of metal Stage I with Na, Na 2 KandK 2 Na t butanol and t amyl alcohol 40 87 reflux 81
M-SG Solvent Compatibility Solvent Prod. (%) THF 81 Me-THF 85 Dioxane 76 MTBE 75 DMSO 3 Solvent Prod. (%) Cyclohexane 83 Heptane 82 DME 67 EtOAc 0 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 Entry Substrate Major Product Rxn Equiv. Time (h) Na-SG(I) Prod./Yield (%) Na/NH 3 (lit.) Prod./Yield (%) 1 35 3.5 20 2.0 96 / 70 --/85 2 2.0 1.0 87 / 83 - - / 97 3 35 3.5 25 2.5 99 / 94 --/96
Aromatic Hydrocarbons Entry Substrate Major Product Rxn Equiv Time (h) Na-SG(I) Na/NH 3 (lit.) Prod./Yield (%) Prod./Yield (%) 1 3.5 2.0 100 / 83 - - / 80-90 2 35 3.5 20 2.0 100 / 82 --/8090 80-90 3 14 24 9 / - - - - / 63
Aryl Ethers Entry Substrate Major Product Rxn Equiv Time (h) Na-SG(I) Na/NH 3 (lit.) Prod./Yield (%) Prod./Yield (%) 1 14 24 30 / - - - - / 74 OMe 2 35 3.5 24 12 / - - - - /19 OMe 3 3.5 24 68 / 43 - - / - - 4 14 24 85 / 68 --/74 5 5.6 24 - - / 56 --/ -- 6 3.5 2.5 92 / 80 - - / 74 (liq. NH 3 )
Polycyclic Aromatic Heterocycles Entry Substrate Major Product Rxn Equiv Time (h) Na-SG(I) Prod./Yield (%) Na/NH 3 (lit.) Prod./Yield (%) Et 1 56 5.6 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 them access to a new product line
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 D 2 O Desired product is isolated in similar yields andpurities NMR integrations shows deuterium incorporation product in 81% yield When performing a reduction with SiGNamaterials, any C H bond formed can be also be converted into a C D bond
SiGNa s Competitive Advantage Sodium Metal (Na 0 ) 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 f f O Nandi, P.; Redko, M. Y.; Petersen, K.; Dye, J. L.; Lefenfeld, 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%
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