This protocol is an efficient method for the synthesis of aminated tropone derivatives. These compounds can serve as synthetic intermediates for the synthesis of structurally complex amines. An advantage of this technique is that the aza-Micheal addition can be accomplished in a solvent free process with many amine substrates.
This simplifies reaction setup and product isolation. Add a PTFE magnetic stir bar, 150 milligrams of tricarbonyl tropone iron and 0.154 milliliters of phenylethylamine to a one dram vial. Cap the vial under an air atmosphere and commence magnetic stirring.
Monitor the reaction periodically by removing a small aliquot from the reaction mixture, dissolving in deuterated chloroform, and acquiring a proton NMR spectrum. Observe for disappearance of the signals for tricarbonyl tropone iron in the proton NMR spectrum. Upon their disappearance, purify the crude reaction mixture via chromatography on basic alumina.
Pack a 30 millimeter diameter chromatography column with alumina and hexanes. Apply the crude reaction mixture to the top of the column. Elute the column with one to one hexanes to diethyl ether to remove the excess phenylethylamine from the column.
Monitor the elution via thin layer chromatography. After the excess amine has finished eluting change the eluting solvent to one to one diethyl ether to methylene chloride to elute the product. Add a PTFE stir bar to 0.021 milliliters of o-toluidene and 1.0 milliliter of diethyl ether to a one dram vial.
Commence vigorous magnetic stirring. Then carefully add 33 milligrams of the cationic complex to the mixture. Allow the suspension to stir for 12 hours.
After 12 hours, pour the reaction mixture into five milliliters of deionized water in a separatory funnel. Then, extract the aqueous layer with 5 milliliters of ethyl acetate three times. Wash the combined organic layers with 10 milliliters of brine before drying over anhydrous sodium sulfate.
Then remove the sodium sulfate by gravity filtration. Concentrate the filtrate via rotary evaporation to obtain the crude product for purification via column chromatography on basic alumina. Dissolve 76 milligrams of amine four in two milliliters of absolute ethanol in a 25 milliliter round-bottom flask under air atmosphere.
Then, add 104 milligrams of di-tert-butyl dicarbonate followed by 40 milligrams of solid sodium bicarbonate to the reaction mixture. Cap the flask with a rubber septum and sonicate the mixture for one hour. Filter the crude reaction mixture through a bed of diatomaceous earth using a Buchner funnel.
Wash the diatomaceous earth with ethanol until no more brown colored solution comes out of the bottom of the funnel. Transfer the filtrate to a round-bottom flask and concentrate on a rotary evaporator. Dissolve the resulting oil in approximately 2.5 milliliters of methylene chloride.
Add approximately 1.3 grams of silica gel to the solution, then remove the methylene chloride on the rotary evaporator until a fine free flowing solid is obtained. Now, pack the silica gel into a 10 gram silica cartridge for automated flash chromatography. Run the column using a gradient starting from 90 to 10 hexanes to ethyl acetate and ending at 20 to 80 hexanes to ethyl acetate over a period of 20 minutes.
Collect the fractions containing the product as indicated by the major peak detected at 254 nanometers absorbance. In a 10 milliliter round-bottom flask dissolve 27 milligrams of iron complex five in one milliliter of methanol under air atmosphere and immerse the flask in an ice bath. Commence magnetic stirring and add 33 milligrams of cerium four ammonium nitrate.
After 30 minutes add a second 33 milligram portion of cerium four ammonium nitrate followed by a third 33 milligram portion after an additional 30 minutes of stirring. After adding the third portion of cerium four ammonium nitrate, dilute the reaction mixture with five milliliters of ethyl acetate. Pour the mixture into a 30 milliliter separatory funnel containing 5 milliliters of saturated aqueous sodium bicarbonate.
Separate the layers. Re-extract the aqueous layer with ethyl acetate. Then, dry the combined organic layers over anhydrous sodium sulfate before performing the final purification steps as described in the text protocol.
The proton NMR data for the cationic iron complex features seven distinct multiplets, including signals arising from diastereotopic alpha methylene protons. Shown here are the proton and carbon 13 NMR data for the o-toluidine adduct three prepared via cationic complex two which contains the same features as the phenylethylamine adduct four. The proton NMR spectrum is characterized by signals arising from the iron complexed diene and the diastereotopic alpha methylene protons.
Shown here are the proton and carbon 13 NMR spectra of tert-butyl carbamate five. The proton NMR spectrum is characterized by its broad peaks caused by slow rotation of the carbamate carbon nitrogen bond relative to the NMR time scale. In addition, the presence of the tert-butyl carbamate is evident from the large singlet at 1.5 ppm from the tert-butyl protons.
As well as the signal at 154.3 ppm in the carbon 13 NMR spectrum corresponding to the carbonyl carbon of the carbamate group. Upon decomplexation of the diene from the iron, the most notable aspect of the proton NMR spectrum is the presence of four signals between 5.75 and 6.75 ppm corresponding to the protons from the uncomplexed diene. The compound synthesized using this protocol contains several functional groups which enables the synthesis of a diverse collection of complex amines that contain a seven membered ring.
This protocol involves the use of flammable solvents and toxic reagents. Reaction and purifications must be performed in a fume hood. Safety glasses and gloves must be worn.
