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

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