This method can provide new insights into the reduction chemistry of lanthanide metals in the field of organic chemistry, as demonstrated in this case in C-F activation reactions. The main advantage of this technique, which can be applied to all lanthanide metals, is that it provides highly reactive metals for a wide range of organic and organo-metallic reactions. Prior to the procedure, synthesize the desired trifluoromethylated benzofulvene and nitroalkene.
The day before the reaction, distill at list two milliliters of anhydrous tetrahydrofuran, and store it over activated molecular sieves. Also, transfer into a nitrogen or argon-filled glove box a metal file, pliers, aluminum foil, a shallow polypropylene container, an oven-dried five milliliter test tube, and two rubber septa. To begin, measure out 65 millimoles of the trifluoromethylated benzofulvene, and place it in an oven-dried 50 milliliter Schlenk tube, equipped with an oven-dried magnetic stir bar.
Close the Schlenk tube with a PTFE-lined plastic screw cap. Clamp the tube over a magnetic stirrer, and connect the side-arm to a Schlenk line. Start stirring at about 700 to 800 rpm, and open the tube to vacuum.
Dry the benzofulvene under vacuum for ten minutes, and then vent the tube with nitrogen or argon gas. Repeat the drying process twice more, for a total of three times. Then, fill the tube with inert gas and close its stopcock.
Transfer the tube to the inert gas-filled glove box. Put one piece of aluminum foil on the balance in the glove box, in place of weighing paper. Line the polypropylene plate with another piece of aluminum foil to catch metal filings.
Then, tightly hold the large piece of dysprosium metal with the pliers. File off the outer, inactive layer of the metal, over the foil-lined plate, being careful to avoid contact between the file and the pliers, to minimize metal contamination. Then, measure 82 milligrams of freshly-filed dysprosium metal.
Place the metal in the Schlenk tube, and stopper the tube with a rubber septum. After that, measure 200 milligrams of anhydrous aluminum chloride into a test tube, and stopper the tube with the second rubber septum. Remove the Schlenk tube and the test tube from the glove box when ready to begin C-F activation.
Clamp the Schlenk tube over a magnetic stirrer, and connect it to the Schlenk line. Perform three cycles of drying the mixture under vacuum for ten minutes, and refilling the tube with inert gas. Then, put the Schlenk tube under a positive pressure flow of inert gas, and start stirring the dry mixture.
Clamp the test tube of aluminum chloride in the hood, and connect the test tube to a positive flow of inert gas via a needle through the septum. Next, add 10-12 milligrams of iodine to the Schlenk tube, under a positive flow of inert gas. Then, purge a dry, plastic, two milliliter syringe, equipped with a 21 gauge, 120 millimeter hypodermic needle, by filling the syringe with inert gas, and expelling it three times.
Draw 1.5 milliliters of the freshly-distilled, dry THF into the purged syringe. Add 5 milliliters of THF to the Schlenk tube, to obtain a deep brown solution. Add the remaining one milliliter of THF drop-wise to the aluminum chloride.
If needed, gently swirl the tube to dissolve the aluminum chloride. Then, draw the still warm, yellow-tinged aluminum chloride solution into the syringe, and add it to the reaction mixture in the Schlenk tube. Continue stirring the reaction mixture until the benzofulvene has been fully consumed, which usually takes about one hour.
The mixture will first become yellow-brown, and will then become turbid, dark green. Meanwhile, measure into an oven-dry test tube 5 millimoles of the desired nitroalkene. Seal the tube with a rubber stopper, and begin drying the nitroalkene under vacuum via a needle through the septum.
After the reaction has proceeded for one hour, take a sample of the mixture with a ten centimeter capillary for thin-layer chromatography. Elute the sample with petroleum ether, and check for a bright yellow spot from benzofulvene. Once the benzofulvene has been consumed, fill the tube of nitroalkene with inert gas.
Then, add the dry nitroalkene to the Schlenk tube, under a positive flow of inert gas. The reaction mixture will become yellow-green. Continue stirring the mixture until the nitroalkene has been consumed, which usually takes about one hour.
Evaluate the nitroalkene consumption via TLC, with a 95 to 5 by volume petroleum ether and ethyl acetate mixture as the eluant. Upon reaction completion, dilute the product mixture with 20 milliliters of diethyl ether. With the Schlenk tube open in the fume hood, quench the mixture with five milliliters of a one-mole-per-liter aqueous solution of hydrochloric acid.
Finally, extract the product into diethyl ether, dry the extract over a magnesium sulfate, and purify the product with silica gel column chromatography. The proposed reaction mechanism involves a lanthanide-mediated CF activation, transmetallation, and nitroalkene addition. Fluorine NMR of the crude product showed two sets of two doublets attributed to the difluroalkene groups of the diastereomeric products.
A small amount of the hydrolysed product was observed, owing to the excess of the starting benzofulvene. A significant amount of hydrolysed product is observed if moisture entered the reaction mixture, or if the reaction was quenched before the completion of nitroalkene addition. Starting material may be observed if C-F activation did not go to completion, which may indicate an insufficiently reactive lanthanide.
The diastereomers could be separated via slow elution, on a long silica gel column. Using dysprosium, the reaction proceeded well, with a range of two nitroalkenes. While 2-thienyl-substituted benzofulvene successfully reacted with para-chlorophenyl nitroalkene.
No reaction occurred under similar conditions if benzofulvene was substituted with the electron-rich para-dimethylamino phenyl group. After watching this video, you should have a good understanding of how to handle reactive lanthanide metals under inert atmosphere, and how to use the strong reduction potential for interesting and synthetic procedures.
