Org Prep Daily

February 16, 2010

4-(2′-bromoethyl)-3-chloro-2-inolinone from isochromane

Filed under: procedures — milkshake @ 11:44 am

1) 2-(2′-bromoethyl)-benzaldehyde:

A solution of isochroman 25.30g (188.5 mmol) in acetic acid 100mL was cooled on ice-water bath. 33% HBr in acetic acid 3.0mL was added followed by a “tip of spatula” amount of solid AIBN, followed by neat bromine 10.0 mL over 10 min (carefully!). The mixture was stirred on ambient water bath for 1 day. 33% HBr in acetic acid 50mL was then added and the mix was refluxed on a 90C oil bath for 30 min. Acetic acid and HBr was then removed carefully by vacuum distillation first at 50 Torr from 90C bath, and then at 15 Torr/90C. The obtained residue was then distilled at 0.6 Torr from 90 -140C oil bath. The main fraction distilled  at 105C/0.6 Torr. Y=34.35g (85.5% th) of a pale blue oily liquid that is somewhat impure (about 15% impurity) and it is best used immediately for the next step.

2) 2-(2′-bromoethyl)-beta-nitrostyrene:

A mixture of methanol 100mL and 25% wt methanolic sodium methoxide solution 1.0mL (Aldrich) was cooled on ice bath and nitromethane 9.0mL was added, followed by neat crude 2-(2′-bromoethyl)-benzaldehyde 25.89g (121.5 mmol) from the previous step. (The flask containing the aldehyde was washed with a portion of the reaction mixture and the washings were added back to the reaction mixture). The reaction mix was stirred on ice for 10 min, then additional 25% wt sodium methoxide in methanol 33mL (=30g) was added over 10 min and the stirring on ice was continued for 90 min.  Meanwhile 600mL of 6M HCl (conc. HCl + water 1:1 by volume)  in a large beaker was chilled on ice bath. The reaction mix was poured into cold stirred 6M HCl in a thin stream and the resulting sludge was stirred on ice for 30 min. The solids were collected by filtration using a large glass Buchner funnel, washed thoroughly with ice-cold water, then rinsed with a small volume of cold hexane (about 20mL) on the Buchner funnel, dried by suction and on highvac. The crude product was re-dissolved in hot benzene 30mL and the solution was gradually diluted with cyclohexane 250mL at reflux and the solution was then allowed to crystallize overnight. The crystalline precipitate was collected by filtration, washed with hexane and dried on highvac. This provided 13.88g of pure nitrostyrene product. Additional 5.673g of pure product was obtained by concentrating the supernatants and purifying the residue on a column of silica (100g) in 3:1 hexane-ethyl acetate. (The zone of the purified product on silica has a tendency to crystallize on he column so it is advisable to avoid using Combiflash and work reasonably fast. ) Combined Y= 19.553g (63% th)

4-(2′-bromoethyl)-3-chloro-2-indolinone;

Anhydrous FeCl3 30g was suspended in anhydrous dichloromethane 450mL under Ar and cooled to -18C on ice/salt slush. Acetyl chloride 9.0mL was added dropwise and the mixture was stirred for 15 min. The nitrostyrene from the previous step, 15.77g (61.57 mmol) dissolved in anh. dichloromethane 50mL was then slowly added through a canula over 20 min at -18C. After additional 45 min at -18C the mix was placed on ice bath and stirred at 0C for 4 hours 30 min. The reaction mix was  then poured onto crushed ice 300g in a large beaker and the mix was stirred for 45 min. The obtained biphasic mix was filtered through a 150mL glass medium-porosity Buchner funnel, the obtained precipitate was thoroughly washed with water and then with small volume of chilled dichloromethane (2x10mL)  to provide 4.498g of pure product as a off-white powder. The combined filtrates were separated, the organic phases were washed with half-saturated NaCl aq. solution. The aqueous phases were re-extracted with dichloromethane (3x300mL). The combined organic extracts were dried (MgSO4) and concentrated down to about 100mL volume, then placed to a fridge (0C) overnight. The precipitated second crop was collected by filtration, washed with a small volume of chilled dichloromethane and dried. This provided 4.139g of pure product. A third crop 1.250g was obtained by applying the supernatants on a column of silica (80g) and eluting with EtOAc gradient in DCM, 0 to 20% EtOAc, UV detection @261 nm. The combined Y=9.887g (56.5% th)

1H(d6-DMSO, 400MHz): 10.787(s, 1H), 7.275(t, 7.8Hz, 1H), 6.968(d, 7.8Hz, 1H), 6.778(d, 7.7Hz, 1H), 5.708(s, 1H), 3.755(m, 2H), 3.217(m, 2H)

February 15, 2010

4-(2′-bromoethyl)-2-indolinone by chemoselective transfer hydrogenation

Filed under: procedures — milkshake @ 2:15 pm

4-(2′-bromoethyl)-3-chloro-2-indolinone 3.00g (10.93 mmol) and Pd-C 300mg [10% Pd on charcoal, Aldrich] was suspended in ethyl acetate 50 mL in a round flask and the mixture was brought to reflux on a 100C bath with vigorous stitting. A solution of NaH2PO2.H2O 3.0g in water 12ml was gradually added through the condenser over a 30 min period. After the complete hypophosphite addition the mix was stirred at reflux for additional 2 hours, then cooled to about 40C and filtered while warm to remove the catalyst. (The spent catalyst was washed with additional water 100mL and EtOAc 100mL). The combined filtrates were separated, the aqueous phase was re-extracted with another portion of EtOAc (100mL). The combined organic extracts were dried (MgSO4) and evaporated. The solid residue was suspended in EtOAc 20mL, the solids were collected by filtration, washed with freezer-chilled EtOAc and dried by suction and on highvac, to provide the 1.428g of a pure product. A second crop 0.850g (95% pure by HPLC) was obtained by evaporating the supernatants and re-crystallizing the residue from EtOAc 10mL (reflux, then RT, then 0C fridge overnight). The combined Y=2.278g of a white crystalline solid (87% th)

1H-NMR (d6-DMSO, 400MHz): 10.360(s, 1H), 7.123(t, 7.8Hz, 1H), 6.848(d, 7.6Hz, 1H), 6.702(d, 7.7Hz, 1H), 3.720(t, 7.4Hz, 2H), 3.505(s, 2H), 3.054(t, 7.3Hz, 2H)

Note: Sodium hypophosphite is on the DEA-watched precursors list in US because it could be supposedly used as a red P replacement in home manufacture of meth. Since hypophosphite has only limited chemistry uses and the chemistry supplier may not be familiar with its application in the transfer hydrogenation, the shipment can be held up. So put it on a separate order, prepare an explanation with a literature reference, and expect that the order shipment can be delayed for 1-2 weeks until the baloney gets sorted out. (To speed things along be ready to complain to the supplier that they are concerned with pleasing the government instead of their customers).

February 14, 2010

Fisher indole synthesis

Filed under: procedures — milkshake @ 6:27 pm

5-chloro-2-hydroxyacetophenone 5.655g (33.15 mmol) and 10 drops of acetic acid in a 0.5L round flask was combined with absolute EtOH 20mL and phenylhydrazine 3.60mL (4.031g; 37.3 mmol) was added. The mixture was stirred on a 80C bath for 75 min and the resulting slurry was evaporated to dryness on rotovap. The solid hydrazone intermediate was dried briefly on highvac, then neat methanesulfonic acid 20mL was added and the mix was stirred on 80C bath until complete dissolution. The bath temperature was then raised to 120C and the mix was stirred at 120C for 1 hour, then cooled to ambient temperature. A large excess of ice-cold water (about 400mL) was added to the mix, the resulting sticky slurry was cooled on ice bath (30 min), the solids were collected by filtration and washed with ice-cold water.  The crude product was dissolved in methanol 50mL at reflux, the solution was gradually diluted with water (450mL) and the mix was stirred for about 20 min, the precipitate was collected by filtration, washed with water and dried by suction. Y=7.706g (95.5% th) of a light-brown crystalline solid, pure by 1H-NMR and HPLC.

Note 1: Phenylhydrazine is exceptionally unhealthy – avoid skin contact.

Note 2: This condensation can be done in one operation as well: 5-fluoro-2-hydroxyacetophenone 5.462g (35.43 mmol) was combined with neat phenylhydrazine 4.334g (40mmol) in a 0.5L round flask and neat methanesulfonic acid 22mL was carefully added. The mixture was stirred on a 80 C bath until the mix became homogennous (15 min) and then at 120 C for one hour, then cooled to ambient temperature.  The rest of the workup is the same as above. The crude product was re-precipitated from a mixture of methanol 150mL and water 300mL as above, to provide 6.130g (76%) of the pure product as a off-white fluffy crystalline solid

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