This method can help to answer key questions in the field of bicyclic aziridinium ion chemistry for the synthesis of various various azaheterocycles including bipyridine and azepine ring systems. The main advantage of this technique is that the synthesis of kai-dal bipyridines and azepine core present in various natural products is achieved in a straight-forward manner. First, add 100 milligrams of the alcohol, 140 microliters of triethylamine, and a magnetic stir bar into an oven dried 25 milliliter two-neck round bottom flask under nitrogen atmosphere.
Using an airtight syringe, add 5 milliliters of anhydrous dichloromethane to the reaction flask. Cool the reaction mixture to 0 degrees Celsius using an ice water bath and stir the mixture for 5 minutes. Next, add 164 milligrams of p-toluenesulfonic anhydride to the reaction mixture and stir for another 45 minutes.
After stirring for 45 minutes, warm the reaction mixture to room temperature and stir for 30 minutes. Monitor the reaction progress by thin layer chromatography using hexanes and ethyl acetate as the eluant. After the complete consumption of the starting alcohol, quench the reaction mixture with 5 milliliters of water.
Then extract the heterogeneous mixture three times with 15 milliliters of dichloromethane. Dry the combined organic layer over anhydrous sodium sulfate for 10 minutes. After filtration, concentrate the filtrate in vacuo using a rotary evaporator.
Purify the crude product by flash-column chromatography using a gradient of hexanes and ethyl acetate to afford the tosylate in 96%yield as a viscous liquid. Now, transfer 5 milligrams of the tosylate in an NMR tube and add 300 microliters of deuterated acetonitrile. Set aside this solution at room temperature for 24 hours to attain complete conversion to the azoniabicyclo.
Monitor the conversion by NMR at different time points. Add 160 milligrams of the previously prepared tosylate and a magnetic stir bar into an oven-dried 25 milliliter round-bottom flask. Using an airtight syringe, add 4 milliliters of anhydrous acetonitrile to the reaction flask.
Add three equivalents of a suitable nucleophile to the reaction mixture and stir for 8 to 15 hours. Once the reaction is complete, quench the mixture with 5 milliliters of water. Then extract three times with 15 milliliters of dichloromethane.
Dry the combined organic layer over anhydrous sodium sulfate. After filtration, concentrate the filtrate in vacuo using a rotary evaporator. Purify the crude product by column chromatography using a gradient of hexanes and ethyl acetate to afford the pure ring expanded products.
Transfer 100 milligrams of the aziridinyl tosylate and a magnetic stir bar into an oven dried 25 milliliter round-bottom flask fitted with a reflux condenser. Using a syringe, add 4 milliliters of 1, 4-dioxane to the reaction flask. Add 0.4 milliliters of 2 molar sodium hydroxide solution to the reaction mixture and heat to reflux for 2 hours.
Once the reaction is complete, quench the mixture with 4 milliliters of water. Then extract the reaction mixture four times with 15 milliliters of dichloromethane. Dry the combined organic layer over anhydrous sodium sulfate.
After filtration, concentrate the filtrate in vacuo using a rotary evaporator. Purify the crude product by column chromatography using a gradient of hexanes and ethyl acetate to afford the pure hydroxy-azepane in a 97%yield. Transfer 220 milligrams of the aziridinyl alcohol, 180 microliters of triethylamine, and a magnetic stir bar into an oven-dried 25 milliliter two-neck round-bottom flask under nitrogen atmosphere.
Using an airtight syringe, add 4 milliliters of anhydrous dichloromethane to the reaction flask. Cool the reaction mixture to 0 degrees Celsius, and stir for 5 minutes. Following this, add 200 milligrams of p-toluenesulfonic anhydride to the reaction mixture, and stir for another 45 minutes.
Then warm the reaction mixture to room temperature, and stir for 30 minutes. Monitor the reaction progress by thin layer chromatography using hexanes and ethyl acetate as the eluant. After the complete consumption of the alcohol, quench the reaction mixture with 5 milliliters of water.
Then extract three times with 15 milliliters of dichloromethane. Dry the combined organic layer over anhydrous sodium sulfate. After filtration, concentrate the filtrate in vacuo using a rotary evaporator.
Now, transfer the crude tosylate and a magnetic stir bar into an oven-dried 25 milliliter round-bottom flask. Using an airtight syringe, add 4 milliliters of anhydrous acetonitrile to the reaction flask. Next, add 125 milligrams of sodium acetate to the reaction mixture and stir for 12 hours.
Once the reaction is complete, quench the mixture with 5 milliliters of water. Then extract three times with 15 milliliters of dichloromethane. Dry the combined organic layer over anhydrous sodium sulfate.
After filtration, concentrate the filtrate in vacuo using a rotary evaporator. Finally, purify the crude product by column chromatography using a gradient of hexanes and ethyl acetate to afford the pure substituted properidine in 83%yield. The proton NMR spectrum of tosylate-2 at different time intervals shows the conversion to azoniabicyclo.
A quartet at 4.07 PPM in the NMR spectrum of ring expanded product 5a corresponds to the CH proton of phenylethyl group. A similar quartet at 3.81 PPM was observed for ring expanded product 6a. The aziridine ring expansion of cyanide, thiocyanide, and acetate nucleophiles afforded properidine rings, while azide, hydroxide, and amine nucleophiles yielded azepane rings.
Synthesis of natural azasugar d-fagomine and its three epimer was achieved by ring expansion of aziridinyl-alcohol-7, followed by removal of the protecting groups to afford the product in 94%yield. Benzyl protected alcohol-10 was treated with p-toluenesulfonic anhydride and triethylamine followed by nucleophilic ring opening resulting in the ring-expanded cyanomethyl-properidine-11 in 90%yield as a single isomer. The ring expansion of alcohol-13 followed by reaction with sodium azide yielded hydroxy-azapane-14 which was used for the azepane core of Balanol by one-pot benzyl deprotection and azide reduction under catalytic hydrogenation.
Once mastered, this technique for aziridine ring expansion can be done in six to eight hours if it is performed properly. While attempting this procedure, it is important to remember to use para-toluenesulfonic anhydride, because it is more sensitive to moisture. Following this procedure, other methods like use of para-toluenesulfonic chloride instead of para-toluenesulfonic anhydride can be used in order to explore the eco-friendly nature of the pro-gen protocol.
After its development, this technique paved the way for the researchers in the field of synthetic organic chemistry to explore the environment of aziridinium ion in azaheterocycles and natural product synthesis. After watching this video, you should have a good understanding of how to use bicyclic aziridinium ion chemistry for the synthesis of biologically-relevant molecules having an azaheterocycles including a variety of natural products. Don't forget that working with toxic reagents such as sodium cyanide used in the synthesis as a nucleophile can be extremely hazardous, and extreme safety precautions should always be taken while performing this procedure.
