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june 2010 org prep daily org prep daily june 22 2010 s 6 methoxychromane 3 carboxylic acid by asymmetric hydrogenation filed under procedures milkshake 1 13 pm 6 methoxychromene 3 carboxylic acid 6 186g 30 mmol and r octahydro binap rucl2 1 2me2nh2 cl complex 26mg from strem takasago made 0 030 mmol ru was loaded into a 300ml sized ace glass pressure hydrogenation flask with teflon screw cap and a rod stirbar the gas inlet was equipped with a rubber septa and the solid mix was flushed with a gentle stream of argon 15 min a solution of cesium formate 21 35g 120 mmol in methanol 120ml in a septum fitted round flask was deoxygenated by argon sparge on ultrasonic bath 15 min bubbling and the solution was transferred into the hydrogenation flask via thick canula under ar the parr hydrogenator gas inlet was connected to the flask the flask was placed on ambient bath on a stirplate behind a blast shield and the argon was replaced with hydrogen 5 times vacuum hydrogen purge the heating was turned on and the mixture was stirred at 40c under 100 psi 7 atm of hydrogen for 20 hours the resulting colorless homogeneous mixture was cooled to ambient temperature carefully vented transferred into a 1l round flask and evaporated to dryness the residue was diluted with water 200ml and dichloromethane 200ml acidified with 6m hcl 30ml shaken and separated the aqueous phases were re extracted with additional dichloromethane 200ml the organic extracts were washed with water 200ml combined dried mgso4 and evaporated to provide 6 30 g of white solid 89 ee by chiral hplc note 1 this not quite pure s acid was dissolved in acetonitrile 1 75l the solution was brought close to reflux and s s chloramphenicol base 6 360g 30 mmol was added in one portion the funnel was washed with additional mecn 30ml and the mix was stirred at gentle reflux until complete dissolution 15 min the mix was then allowed to crystallize at ambient temperature overnight 16 hours the precipitated salt was collected by filtration washed with mecn and dried by suction to provide 11 008g of a pale yellow solid 87 5 th 99 ee note 2 this chloramphenicol base salt was combined with ether 250ml and water 200ml acidified with 6m hcl 10ml and stirred for 10 min then separated the aqueous phase was re extracted with ether 250ml the organic extracts were washed with water 250ml combined dried mgso4 and evaporated the residue was dried on highvac y 5 455g 87 of a white crystalline solid 99 ee note 1 chiral reverse phase column chiralpak ad rh was used at 0 85ml min flow column thermostat temperature 70c in water acetonitrile shallow gradient about 15 20 mecn with 0 1 tfa present in the buffer the s enantiomer elutes first followed by r note 2 if the chloramphenicol base salt is re crystallized from acetonitrile for the second time a product with no detectable minor enantiomer 99 ee is obtained but the recrystallization takes quite a lot of acetonitrile and 99 ee was good enough note 3 100 psi is more than what is recommended for the parr shaker equipment it is certified only up to 50 psi i managed behind a protective shield without a mishap but using a steel autoclave would be probably a safer alternative there is almost no conversion if the hydrogenation is attempted under h2 baloon note 4 s s mandyphos sl m004 1 in combination with rh nbd 2 bf4 at subst catalyst 100 1 ratio gave with this substrate 84 85 ee of r enantiomer in meoh at room temp and 100psi h2 within 2 h 15 min and complete conversion and no formate additive was necessary the rh source salt is however fairly air sensitive as a solid and the active pre catalyst solution of the phosphine rh complex in meoh is tricky to handle without a glovebox i had reproducibility problems with hydrogenations run at low catalyst loadings the hydrogenations often stalled on the other hand the octahydrobinap rucl2 complex comes ready made it is stable enough to be weighted out in air and it can be loaded as a solid unlike ru acetate phosphine complexes ru halide phosphine complexes are robust but lazy the exchange of halide with formate activates them in situ other formate salts such as hco2na can be also used and less than 0 5 equiv of formate is needed but adding more formate salt seems to improve the ee by few cs formate is readily soluble in methanol and it also appears to provide a marginally better ee the starting chromene acid preparation is described here comments 24 pages about milkshake about org prep daily bug report chemistry resources chemistry chemjobber in the pipeline med chemist open flask org chem portal practical fragments stellen fuer chemiker edible links serious eats links to behold idle words categories chris douglas industry life krest17 lab destruction lit highlights mechanisms procedures questions uncategorized search archives january 2026 december 2025 november 2025 october 2025 september 2025 april 2019 march 2019 december 2018 june 2018 september 2017 august 2017 march 2016 october 2015 august 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