This thesis from Drexel University in 2013 describes the synthesis of various nitro compounds. It details the formation of Michael donors from lithium nitrate and sodium carbonate reactions with compounds like 2-methyl-2-butene. These donors undergo Michael additions with methyl acrylate catalyzed by DBU. The resulting products are then reduced using nickel chloride and sodium borohydride, forming cyclic compounds in spontaneous ring closures. The yields for the reduction step were low, around 10-16%, possibly due to recrystallization issues. The thesis suggests finding alternative purification methods and testing new Michael donors, such as from isobutene, to create analogs with potential bioactivity similar to the drug Keppra

4. Paparoidamis, Nicholas, and Peter A. Wade. "Chemistry of Allyl Nitrate Esters, β-Nitroacetamides, and
Various Other Nitro Compounds." Thesis. Drexel University, 2013.

5. Paparoidamis, Nicholas, and Peter A. Wade. "Chemistry of Allyl Nitrate Esters, β-Nitroacetamides, and
Various Other Nitro Compounds." Thesis. Drexel University, 2013.

12. Methyl acrylateN-(2-methyl-3-nitrobutan-2-yl)acetamide

15. methyl 5-(acetylamino)-4,5-dimethyl-4-nitrohexanoate

17. N-[2-(2-methyl-5-oxopyrrolidin-2-yl)propan-2-yl]acetamide

18. Formation of Michael Donor (under N2 ):
-Anhydrous Acetonitrile (160 ml)
-Lithium Nitrate (10 g)
-Trifluoroacetic Anhydride (11.2 ml)
-Allowed 30 minutes to form solution via mixing
-Cool to approximately 0° C
-Sodium Carbonate (8.48 g)

19. Formation of Michael Donor (under N2 ):
-2-methyl-2-butene (4 ml)
-Allowed 12 hrs of mixing
-Addition of 200 ml of water
-Extraction with methylene chloride
-Spontaneous formation of crystals via removal of solvent
-Recrystallized in a warm solution of chloroform and toluene (1:3)
-Typically Observed yield around 50%

20. Michael Addition
-Tetrahydrofuran (5 ml)
-Michael Donor product (1 g)
-Methyl acrylate (0.55 ml)
-DBU [1,8-Diazabicyclo[5.4.0]undec-7-ene] (0.85 ml)
-Allowed 18 hrs under mixing
-Added to 100 ml of methylene chloride
-Extracted organic layer after washing with 50 ml of 1.2% HCl solution
-After removal of solvent recrystallized in warm chloroform/toluene (1:3)
-Crystals formed overnight at 0° C
-Typically observed yield around 59 %

21. Nitro Reduction and Product Formation
-Methanol (50 ml)
-Nickel Chloride (0.6138 g)
-Sodium Borohydride (0.3344 g)
-Michael Addition Product (0.95 g)
-Sodium Borohydride (0.7790 g)
-Allowed 4 - 6 hrs under mixing

22. Nitro Reduction and Product Formation
-Filtered through celite and solvent removed
-Added 50 ml of methylene chloride and filtered
-Dried with magnesium sulfate and solvent removed
-Recrystallized in hot chloroform/toluene (1:3)
-Run twice successfully with observed yields of 16.50% and 9.98 %

23. -Reduction reaction appears to take place with spontaneous ring closure.
-Formation of the N-(β-nitroalkyl)acetamide from 2-methyl-2-butene and subsequent
Michael addition is a straightforward method of making the needed starting material
-Yield of cyclized reduction product is rather low perhaps due to problems in
recrystallization
-Finding a suitable mobile phase for column chromatography or HPLC could be used to
better quantifify the amount of product
-NMR and IR spectra indicate successful formation of product but confirmation will be
obtained from mass spec and elemental analysis
-A new Michael donor should be tried. It would be created from isobutene and would be a
closer analog to KeppraTM for potential bioactivity

24. [1] Paparoidamis, Nicholas, and Peter A. Wade. "Chemistry of Allyl Nitrate Esters, β-
Nitroacetamides, and Various Other Nitro Compounds." Thesis. Drexel University, 2013.