Swern-Moffatt oxidation

Oxidation with dimethyl sulfoxide (DMSO), which is known as Swern-Moffatt oxidation, is one of the most versatile and reliable methods for the oxidation of alcohols to carbonyl compounds and is widely utilized in laboratory organic synthesis. Avoidance of heavy metals such as Mn and 

Cr is also advantageous from an environmental point of view. Various methods for the activation of DMSO have been developed, and activation with trifluoroacetic anhydride (TFAA) is frequently employed in modern organic synthesis. It is well known that a reactive species generated by the 

It is important to note that the first step and the second step are relatively fast. In a macrobatch system, however, it takes time (a minute or so) to complete the addition of a reagent or a substrate. During that time the reactive intermediate might decompose. In a microflow system, however, the reaction time can be greatly reduced to avoid decomposition of the unstable reactive intermediates. The concept of reactive intermediate control based on a short residence time, which we have already discussed in Chapter 6, can be applied in this case. 

Attempts to further increase the reaction temperature, however, leads to lower yields of the desired carbonyl compounds (32% for cyclohexanol at 0 °C). Presumably, Pummerer rearrangement of the reactive species I takes place to give II at this temperature within the residence time of 2.4 s. The 

Method Residence Temperature Conversion Selectivity Selectivity Selectivity time ( C) (%) of ofMTM ofTFA 

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Scheme 8.6 Proposed mechanism for Swern-Moffatt oxidation using TFAA...

A mechanism suggested for Swern-Moffatt oxidation with TFAA is shown in Scheme 8.6. In the first step, DMSO reacts with TFAA to form cationic reactive species I, which is known to be stable only below —At higher temperatures, rearrangement of I takes place to give species II. The reaction of II with an alcohol IQ upon treatment with a base leads to formation of a major by-product, trifluoroacetic acid (TFA) ester VII. Therefore, the first step should be carried out below —50 °C. In the second step, reactive species I is allowed to react with an alcohol HI at or below —50°C to obtain intermediate IV. IV may also undergo the Pummerer rearrangement to give a methyl thiomethyl (MTM) ether VI upon treatment with a base. In the third step, IV is treated with a base (usually triethylamine) to obtain the desired carbonyl compound V and dimethyl sulfide. 

Table 8.3 Swern-Moffatt oxidation of cyclohexanol using a microflow system and a macrobatch system...

The Swern-MofFatt oxidation is a versatile metal-free oxidation method that finds application in the transformation of primary and secondary alcohols into aldehydes and ketones, respectively. However, its application in process chemistry is hampered by the low-temperature requirement, namely, 70 °C, and the highly exothermic behavior, which makes temperature control very diEBcult. The highly efficient heat transfer in the microreactor should solve the problem of limited cooling capacity in a batch reactor. 

The microreactor could also serve as a tool for quick scale-up of Swern-Moffatt oxidations. The scalability and reliability of the microreactor were tested by running the system for several hours. For testosterone, the system was operated for 1.5 h, resulting in an 4-androstene-3,17-dione production rate of 64g/h. 

All of the usual chromium-based oxidation reagents that have been used for the oxidation of cyclobutanols to cyclobutanones, for example, chromium(VI) oxide (Jones reagent),302 pyri-dinium chlorochromate,304 pyridinium dichromate,307 and chromium(YI) oxide/pyridine (Collins),303 are reported to do so without any serious problems. Alternatively, tetrapropylam-monium perruthenate in the presence of A-methylmorpholine A -oxide. oxalyl chloride in the presence of triethylamine in dimethyl sulfoxide (Swern),158,309,310 or phenyl dichlorophos-phate in the presence of triethylamine and dimethyl sulfoxide in dichloromethane (Pfitzner-Moffatt),308 can be used. The Pfitzner-Moffatt oxidation procedure is found to be more convenient than the Swern oxidation procedure, especially with respect to the strict temperature control that is necessary to achieve good yields in the latter, e.g. oxidation of 1 to give 2.308... 

Omura-Sharma-Swern Oxidation (TFAA-Mediated Moffatt Oxidation)... 

In an enantioselective synthesis of a key intermediate for the preparation of poisons from the skin of tropical frogs, a key oxidation was performed under Swern conditions with 77% yield, while PCC provided a 28% yield and Pfitzner-Moffatt oxidation 73% yield. 

But the Pfitzner-Moffatt oxidation is not in much use because the Swern oxidation gives better yield and fewer side products. For example, methyl 12-hydroxydodecanoate (7.11) on treatment with DMSO and oxalyl chloride [(COCl)2] in CF12C12 followed by treatment with triethylamine yields 87% methyl 12-oxododecanoate (7.12). 

Related reactions Dess-Martin oxidation, Jones oxidation, Ley oxidation, Oppenauer oxidation, PTitzner-Moffatt oxidation, Swern oxidation ... 

This reaction is related to the Dess-Martin Oxidation, Swern Oxidation, and Pfitzner-Moffatt Oxidation. 

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... 

Oxidation of Alcohols to Carbonyl Compounds with Activated Dimethyl Sulfoxide via Alkoxysulfonium Ylides. The Swern, Moffatt, and Related Oxidations... 

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 oxidation that proved troublesome under a variety of conditions, like Swern, PCC, Dess-Martin and Parikh-Doering, succeeded under Pfitzner-Moffatt conditions. 

Primary alcohols possess a substantially less crowded environment than secondary ones. Thus, in the absence of dominant electronic factors, many oxidants tend to react quicker with primary alcohols. These include many common oxidants, like TPAP,1 PCC,2 Parikh-Moffatt,3 Dess-Martin,4 IBX5 and Swern,6 that are sometimes able to perform selective oxidations of primary alcohols in useful yields, regardless of the fact that they were not devised for this purpose. 

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