Hello,
This is the closest thread I could find related to borane. This is not exactly free borane being used but the formation of BH3*THF in situ, which I'm sure many have heard about, but there is hardly any experimental information around. Well, the method works alright and what follows is its application in the synthesis of Aleph, 4-methylthio-2,5-dimethoxyphenylaminopropane. The synthesis of some of the precursors is also included. 2,5-dihydroxythiophenol was made from 5-hydroxy-1,3-benzoxathiol-2-one, this information is available elsewhere.
The yield on methylation was lower than reported in the Me3PO4 thread because it was done through the night and stirring had stopped as the RM became too thick. At least that is my theory.
2-methylthio-1,4-dimethoxybenzene
In a 250ml 3-neck RBF w/stirbar, condenser, thermometer, Ar inlet and bubbler was added trimethyl phosphate (4eq, 400mmol, 56g) and there was added in a single portion 2,5-dihydroxythiophenol (14.22g, 100mmol) and this stirred until dissolution. A pale yellow solution resulted. In a single portion there was added anhydrous, powdered K2CO3 (3.1eq, 310mmol, 42.84g) which resulted in a very strong exotherm and foaming, but it stayed under control, it should be added in a few portions for safety.
The greenish slurry was heated overnight (~8h) on a boiling water bath. The next day the thick, unstirrable, light brown mass was cooled transferred to a sep funnel with the aid of 250ml H2O.
The mixture was extracted with EtOAc (3x50ml), the organic layer washed with H2O (100ml), 5% aq NaOH (2x 50ml), H2O (2x100ml) and finally brine (50ml). The solvent was filtered through a plug of silica (30g) which removed much color. The orange filtrate was evaporated to give an amber oil weighing 16.19g, MW 184, 88mmol, 88% yield.
4-methylthio-2,5-dimethoxybenzaldehyde
The above substituted benzene was transferred to a 500ml RBF with the help of AcOH (150ml). With stirring there was added hexamethylenetetramine (2eq, 176mmol, 24.64g) and this stirred to dissolution, the flask was heated to about 50C to achieve this. After cooling to 15C in an ice bath there was added dropwise during about 10 minutes conc. H2SO4 (4eq, 352mmol, 34.5g) taking care to not allow clumping which occurs if it is added too quickly.
A thick white ppt formed and the bath was removed, then the flask heated to reflux. The mixture became yellow as reflux temperature was reached, then the mixture foams a little and the ppt dissolved within 10 minutes to give a deep red, yellow staining solution.
After 1 hour of reflux the heat was removed and the still hot mixture poured into H2O (250ml) that was warm and kept stirring. The transfer was completed using additional H2O (50ml).
After stirring overnight the white precipitate was filtered, washed with H2O (100ml) and portions of cold MeOH (~40ml total).
The resulting product was dried to give 14.67g of white, fine crystals with a slight sulfide/onion odor that is not strong or irritating. MW 212.26, 78.5% yield. Mp 100-103C
4-methylthio-2,5-dimethoxyphenylnitropropene
To a 100ml 3-neck RBF containing a stirbar and fitted with thermometer, condenser and drying tube was added 4-methylthio-2,5-dimethoxybenzaldehyde (5.30g, 25mmol) followed by iPrOH (25ml) and this stirred and heated to 60C to dissolution. There was then added nitroethane (2eq, 50mmol, 3.58ml), AcOH (800ul) and finally ethylenediamine (170ul, ~10mol%).
This solution was stirred at 75-80C for 1 hour and 10 minutes (ppt occurs at 1h mark) then heat turned off and the flask left stirring (minus water bath, just over the plate) for a further 30 mins.
The flask was then cooled in the freezer for 30 minutes and the crystals filtered and washed with cold iPrOH.
Recrystallization is probably not necessary as the mp is spot on at this point at 137-138C.
The "crude yield" was 5.867g, MW 269.31, 87% yield. The orange product was recrystallized from 150ml iPrOH together with several ml EtOAc to bring all solids into solution, and hot filtered through a cotton plug. After cooling overnight and standing in the freezer for an hour the product is filtered, washed with some iPrOH and dried to give 5.154g of orange needles, mp the same. 76.5% yield after reX.
4-methylthio-2,5-dimethoxyphenylaminopropane hydrochloride
The following reaction was conducted under argon in a closed system (bubbler) with a tube venting outside to remove any free borane that escapes and to prevent an explosion. The dry iodine can be made by melting crude I2 made from an iodide salt under conc H2SO4, decanting the acid and sublimating.
A dry, 250ml 3-neck RBF containing a stirbar was fitted with thermometer, condenser, drying tube, bubbler, Ar inlet and septa and the setup flame dried under a stream of Ar. There was added THF (anhydrous, dist. from LiAlH4, 20ml) and NaBH4 (4.6eq, 46mmol, 1.74g) and this stirred in a salt ice bath to below 0C.
Once at this temperature, dry Iodine (2eq, 20mmol, 2.54g) In THF (15ml) was added carefully, dropwise, over 30 minutes keeping the temp at or below 0C.
Once the addition was complete, the white mixture was stirred without cooling for 30 minutes longer. After this time a solution of the nitropropene (10mmol, 2.69g) in THF (35ml used, with occasional warming to keep in solution) was added during 10 minutes at RT, then the mixture heated to reflux for 5h at which point the color is gone.
Very carefully via syringe there was added dropwise with good stirring/cooling H2O (50ml). At first it is added slowly dropwise, letting the vigorous reaction settle. Then there is added over a few minutes a mixture of conc HCl in H2O (10/40ml) which results in some bubbling. This is then stirred at reflux for 2h to destroy the complex, the THF evaporated in vacuo, and the aqueous solution washed with PhMe (2x 15ml) which removed minimal color. The solution was then basified with excess NaOH solution which precipitated a white product, and it was extracted with PhMe (3x 50ml) and the organic layer washed with H2O (2x 100ml) then brine (30ml).
The slightly cloudy organic layer was filtered though 2cm of Na2SO4 and the solvent removed in vacuo. The thick pale yellow oil was taken in 20ml 96% EtOH, neutralized with conc HCl and diluted with Et2O (80ml) and left for 3h at RT.
The crystals were freed and triturated, left another 30 minutes and filtered, washing with 80ml Et2O. There remained 1.176g of fine, snow white crystals. MW HCl salt: 277.81, 4.2mmol, 42% yield, Mp 200-203 (lit 204-205), bioactivity confirmed.
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So it works, yield is not huge, but I have seen many procedures using BF3*Et2O with NaBH4 that do not yield too high (40-60%). Just another method to apply if you need. It would be very interesting to try a similar procedure utilizing H2SO4 instead of iodine which also reportedly can create BH3*THF.