The overall goal of this experiment is to use a one-pot procedure to synthesize trichloroacetimidates directly from azido nitrate-esters with minimal workup in purification. This method poses clear advantages for the synthesis of trichloroacetimidate donors for use in oligosaccharide synthesis directly from azido nitrate-esters. The main advantage of this technique is that it is faster, cleaner and greener than previously reported methods.
To begin the procedure, place 0.2 millimoles of the chosen azido nitrate-ester in an eight milliliter microwave reaction vial. Dissolve the azido nitrate-ester in two milliliters of 20%aqueous acetone. Add to the reaction vial 0.08 milliliters of pyridine and cap the vial.
Place the vial in a microwave reactor and ramp the reaction mixture to 120 degrees Celsius over the course of two minutes. Irradiate the mixture at 110 degrees Celsius while stirring for fixed whole time of 10 minutes. Then spot the mixture on a TLC plate, and run the plate with a one to one solution of ethyl acetate and hexanes.
Visualize the plate with a ceric ammonium molybdate stain. Verify that the starting material has been completely consumed. Using an airline, evaporate the solvent to a reduced volume.
Then take the reaction mixture off of the airline and dilute the mixture with two milliliters of dichloromethane. Create a vortex with the stir plate. Then use a syringe to remove the water layer.
Finally, cool the reaction mixture to zero degrees Celsius in an ice water bath. Add to the mixture 0.08 milliliters of DBU, and 0.25 milliliters of trichloroacetonitrile. Remove the mixture from the ice water bath and allow the mixture to warm to room temperature while stirring.
Monitor the reaction progress with TLC. Once the anomeric alcohol has been completely consumed, transfer the mixture to a recovery flask. Concentrate the organic layer under vacuum at 30 degrees Celsius to a pale yellow or brown oil.
Finally, purify the crude product by silica gel column chromatography in a 1.5 centimeter column with a one to four mixture of ethyl acetate and hexanes as the eluant. Adjust the eluant proportions as needed for optimal separation. Three, two azido one nitrate-esters were converted to trichloroacetimidates using this procedure.
In each reaction, the microwave assisted thermal denitration was completed within 20 minutes. An 11 to one to six alpha manol, alpha gluco, beta gluco mixture of compound one was converted to a five to one alpha gluco alpha mano mixture of compound three, an 87%overall yield, an 92%alpha only yield. Compound four was converted to compound six in greater than 95%yield.
The hydrolysis of compound four only required 10 minutes of irradiation at 110 degrees Celsius. Conversion of the anomeric alcohol to compound six was achieved in 30 minutes. The overall alpha beta imidate ratio was 34 to one.
A one to 14.4 to 27.4 beta gluco alpha mano alpha gluco mixture of compound seven was converted to a one to 1.7 alpha gluco alpha mano mixture of compound nine, in 68%overall yield, and a 66%alpha only yield. A greater excess of DBU was needed to achieve complete conversion to compound seven. This development allows for the physio transformation of azido nitrate-esters directly to trichloroacetimidate donors in a one-pot synthetic method.
While attempting this procedure, be sure to check the settings on the rotary evaporator and microwave to ensure that using the proper conditions. Once mastered, this technique can be performed in under three hours if done properly. Following this procedure, anomeric characterization can be performed to answer additional questions about the extent of reaction completion prior to workup.
After watching this video, you should have a good understanding of how to synthesize trichloroacetimidate donors directly from the azido nitrate-esters. Remember that working with trichloroacetonitrile can be extremely hazardous. Precautions such as wearing proper PPE should always be taken while following this procedure.
