Swern oxidation side reactions

The bromoallene (-)-kumausallene (62) was isolated in 1983 from the red alga Laurencia nipponica Yamada [64a], The synthesis of the racemic natural product by Overman and co-workers once again employed the SN2 -substitution of a propargyl mesylate with lithium dibromocuprate (Scheme 18.22) [79]. Thus, starting from the unsymmetrically substituted 2,6-dioxabicyclo[3.3.0]octane derivative 69, the first side chain was introduced by Swern oxidation and subsequent Sakurai reaction with the allylsilane 70. The resulting alcohol 71 was protected and the second side chain was attached via diastereoselective addition of a titanium acetylide. The synthesis was concluded by the introduction of two bromine atoms anti-selective S -substitution of the bulky propargyl mesylate 72 was followed by Appel bromination (tetrabromo-methane-triphenylphosphine) of the alcohol derived from deprotection of the bromoallene 73. 

This fluorine-containing, oxidation-resistant alcohol is best oxidized by the Pfitzner-Moffatt reaction, using dichloroacetic acid as catalyst. Observe the use of toluene, instead of carcinogenic benzene, as solvent. A Swern oxidation was not reproducible, and caused substantial epimerization of the isobutyl side chain. Collins oxidation was successful, but ... 

This is a rare case of methylthiomethylation of a primary alcohol during a Swern oxidation. A primary neopentilic alcohol, quite resistant to reaction, was treated under Swern conditions at the temperature of - 10°C. At this temperature, a substantial decomposition of activated DMSO occurred during the activation of the alcohol, resulting in the formation of H2C=S(+)-Me that produced the generation of the methylthiomethyl ether side compound. 

Addition of triethylamine to the activated alcohol, during a Swern oxidation, may produce side reactions, beginning with a deprotonation step. As triethylamine operates at very low temperature, only substrates very sensitive to deprotonation suffer these side reactions. No base-catalyzed hydrolyses are possible because of the absence of water. 

During Swern oxidations, adventitious HC1 may be present either due to the use of impure oxalyl chloride, or due to the hydrolysis of some chlorine-containing chemical, caused by employing wet DMSO. Adventitious HC1 may cause acid-induced side reactions on sensitive substrates.174,246... 

The oxidation of 1,4- and 1,5-diols with many oxidants leads to intermediate hydroxycarbonyl compounds that equilibrate with lactols, which are transformed in situ into lactones. This side reaction is very uncommon during Swern oxidations, due to the sequential nature of alcohol activation versus base-induced transformation of the activated alcohol into a carbonyl compound. Thus, during the oxidation of a diol, normally when the first alcohol is transformed into an aldehyde or ketone, the second alcohol is already protected by activation, resulting in the impossibility of formation of a lactol that could lead to a lactone. 

The disadvantage of the Swern oxidation is the formation of side products from the Pum-merer rearrangement (see section 1.6.1, Scheme 1.26). To avoid the side reactions in the Swern oxidation, the temperature is kept at -78°C, but when trifluoroacetic anhydride instead of oxalyl chloride is used the reaction can be warmed to -30° C. The use of diisopropylamine as a base stops side reactions. 

The efficiency of this oxidation was also evaluated by comparison to other oxidations, such as the Dess-Martin, pyridinium dichromate and Swern oxidations. It was demonstrated that the hypervalent iodine(V)-catalyzed oxidation could be applied for almost all types of fluorinated alcohols and it was comparable to Dess-Martin oxidation, while pyridinium dichromate and Swern oxidations could not be employed for allylic and propargylic alcohols as well as the alcohols having an aliphatic side chain. Additionally, the hypervalent iodine-catalyzed oxidation could be applied for a larger scale reaction (Scheme 4.49) without any decrease in reaction efficiency [81]. 

Microflow systems serve as effective environments to perform various oxidation reactions using chemical reagents. The oxidation using dimethyl sulfoxide (DMSO), which is known as Moffatt-Swern type oxidation, is one of the most versatile and reliable methods for the oxidation of alcohols into carbonyl compounds in laboratory synthesis [1, 2]. However, it is well known that activation of DMSO leads to an inevitable side-reaction, Pummerer rearrangement, at temperatures above — 30°C (Scheme 7.1). Therefore, the reaction is usually carried out at low temperatures (—50 °C or below), where such a side-reaction is very slow [3, 4]. However, the requirement for such low temperatures causes severe limitations in the industrial use of this highly useful reaction. The use of microflow systems solves the problem. For example, the oxidation of cyclohexanol can be accomplished using a microflow... 

Additionally, it must be mentioned that the formation of methylthio-methyl ethers in oxidations with activated DMSO is minimized by the use of solvents of low polarity.123 Hence, the routine use of CH2CI2—which possesses a good balance of solubilizing power versus low polarity—is practiced in Omura-Sharma-Swern and MofTatt oxidations. The formation of side compounds—both trifluoroacetates and methylthiomethyl ethers—is decreased by using more diluted reaction conditions under Procedure C, while concentration has little effect on the yield in oxidations performed under Procedure A.124... 

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