New Approaches in Organic Chemistry

1. Catalyst-Free Oxidation of Sulfides to Sulfoxides by gem-Dihydroperoxide under Mild Conditions
(SynLett, DOI: 10.1055/a-2015-7526)

A facile and efficient method for the oxidation of sulfides (dialkyl, phenylalkyl, benzylalkyl) to sulfoxides under mild conditions without using any catalysts is reported. This method afforded a series of sulfoxides with good yields (>95%). The ready accessibility and low cost of the gem-dihydroperoxides will endow it with attractive applications in chemical synthesis as oxidants.

2. High-Pressure Pathway in the Two-Stage Synthesis of 5-Amino-3-Hydroxy-1-Phenyl-1H-Pyrazole
(Lett. Org. Chem., DOI: 10.2174/0115701786331865241120043030)

5-Amino-3-hydroxy-1-phenyl-1H-pyrazol and 3-amino-5-hydroxy-1-phenyl-1H-pyrazol are widely used as synthons in organic and pharmaceutical chemistry. We developed a high-yield synthesis method for 5-amino-3-hydroxy-1-phenyl-1H-pyrazol using high-pressure and base catalysis, achieving up to 80% yield. This method significantly outperforms existing techniques, which yield no more than 39%. The synthesis was performed at pressures up to 10 katm, both in solvent-free conditions and in the presence of solvents, such as methanol, ethanol, toluene, tert-butyl methyl ether, and 1,4-dioxane. Thermodynamic parameters of possible paths were calculated using the SMD-M06-2X/MG3S method. Applying high pressure (7 katm) enables the solvent-free and catalyst-free synthesis of 2-cyano-N'-phenylacetohydrazide with a yield of 96%. This compound can subsequently be converted into 5-amino-3-hydroxy-1-phenyl-1H-pyrazol with yields of up to 90% using base catalysis. Additionally, the reaction pathways of phenylhydrazine with ethyl cyanoacetate and its anion have been explored. These pathways are discussed in terms of thermodynamic potentials calculated using the SMD-M06-2X/MG3S method. High pressure significantly accelerates the reaction between phenylhydrazine and ethyl cyanoacetate, leading to the formation of 2-cyano-N'-phenylacetohydrazide. This intermediate can then be easily converted into 5-amino-3-hydroxy-1-phenyl-1H-pyrazol. Under neutral conditions, the most favorable reaction pathway involves the attack of the terminal nitrogen of phenylhydrazine on the carbonyl group. In the case of the ethyl cyanoacetate anion, the attack also targets the carbonyl group, but occurs via the phenyl-substituted nitrogen.

3. Epoxidation of Polyunsaturated Fatty Acid Double Bonds by Dioxirane Reagent: Regioselectivity and Lipid Supramolecular Organization
(Helvetica Chimica Acta, DOI: 10.1002/hlca.200690209)

The use of dimethyldioxirane (DMD) as the epoxidizing agent for polyunsaturated fatty acids was investigated. With fatty acid methyl esters, this is a convenient method for avoiding acidic conditions, using different solvents, and simplifying the isolation procedures, with less contamination due to by-products. The reagent was also tested with free fatty acids in water. In this case, the supramolecular organization of fatty acids influenced the reaction outcome, and the epoxidation showed interesting regioselective features. The C=C bonds closest to the aqueous-micelle interface is the most favored for the interaction with dimethyldioxirane. The preferential epoxidation of linoleic acid ((9Z,12Z)-octadeca-9,12-dienoic acid) to the 9,10-monoepoxy derivative was achieved, with a high yield and 65% regioselectivity. In case of arachidonic acid ((5Z,8Z,11Z,14Z)-eicosa-5,8,11,14-tetraenoic acid) micelles, the regioselective outcome with formation of the four possible monoepoxy isomers was studied under different conditions. It resulted to be a convenient synthesis of ‘cis-5,6-epoxyeicosatrienoic acid’ (= 3-[(2Z,5Z,8Z)-tetradeca-2,5,8-trienyl]oxiran-2-butanoic acid), whereas in reverse micelles, epoxidation mostly gave ‘cis-14,15-epoxyeicosatrienoic acid ((5Z,8Z,11Z)-13-(3-pentyloxiran-2-yl)trideca-5,8,11-trienoic acid).

4. A New Synthesis of 5-Hydroxy-6-Methyluracil
(Tetrahedron Letters, DOI: 10.1016/j.tetlet.2012.08.133)

Dehydration of 5,6-dihydro-5,6-dihydroxy-6-methyl- and 5,6-dihydro-5,6-dihydroxy-1,3,6-trimethyluracil in 0.4 M aqueous sulfuric acid gives 5-hydroxy-6-methyl- and 5-hydroxy-1,3,6-trimethyluracil in quantitative yields. Standard DFT calculations at the mPW1k/6-311+G(2df,2pd)//mPW1k/6-31+G(d,p) level have been applied to the question of whether the dehydration of 5,6-dihydro-5,6-diols of uracil derivatives occurred through a C5–C6 hydride shift with the loss of water to a protonated 5,6-dihydro-5-oxo-6-methyluracil derivative, or via an E2 reaction. The latter process was shown to proceed at a substantially lower activation enthalpy and Gibbs free energy than the route through concerted migration of a hydride.

5. Oxidation of Highly Strained Cage Hydrocarbons by Ozone
(Rus. J. Org. Chem., DOI: 10.1134/S1070428015120076)

Optimal conditions for the efficient ozonation of cyclic hydrocarbons have been identified. The reaction primarily affects the weakest C–H bond, leading to the intermediate formation of trioxidanes. In certain cases, ozonation causes cleavage of C–C bonds, resulting in the formation of previously unknown diketones and expanding the scope of oxidative transformations in strained hydrocarbon systems.