Swern oxidation alcohol activation

The 6-endo activated epoxy alcohol cyclization process was also expected to play a central role in the annulation of pyran ring G of the natural product (see Scheme 22). Silylation of the free secondary hydroxyl group in compound 131 furnishes, after hydrobora-tion/oxidation of the double bond, compound 132. Swern oxidation of alcohol 132 produces an aldehyde which reacts efficiently with (ethoxycarbonylethylidene)triphenylphosphorane in the presence of a catalytic amount of benzoic acid in benzene at 50 °C, furnishing... 

Oxidation. DMSO activated by P205 (1 equiv.) and in combination with triethylamine is useful for oxidation of alcohols to ketones and aldehydes, particularly in cases where the Swern reagent results in chlorinated byproducts. Yields are typically 80-85%. 

The Swern oxidation is a preparatively important reaction which allows for the oxidation of primary and secondary alcohols 1 to aldehydes and ketones 2, respectively, under mild conditions, using activated dimethyl sulfoxide (DMSO) as the oxidizing agent. 

Amino-1-fluoro-propylidence)-cyclopentanecarbonitriles (55), i//[CF=C] iso-stere of 2-cyanopyrrolidides, were prepared from 56, an intermediate in the synthesis of 50 (Scheme 19) [65]. A better route was conversion of the primary alcohol (58), another intermediate in the synthesis of 50, to the aldehyde (59) through Swern oxidation followed by treatment with hydroxylamine-O-sulfonicacid (Scheme 10). Both pairs of diastereomer u-55 and 1-55 exhibited inhibitory activity against DPP IV. u-55 and 1-55 also were very stable in buffer (pH 7.6) as assessed by UV-vis spectroscopy over the range of 190-1,100 nm at 30 and 50°C (Scheme 20). 

The oxidation of the primary alcohol leads to an aldehyde that is isolated as an aminal. Minor amounts of a methylthiomethyl ether are isolated, resulting from the reaction of the alcohol with CH2=S(+)-Me that is formed by thermal decomposition of activated DMSO. Interestingly, a Swern oxidation fails to deliver the desire product, because it causes the chlorination of the indole. 

During a Swern oxidation, after the formation of the activated DMSO molecule 30, the alcohol is added at low temperature. The alcohol reacts very quickly with activated DMSO, resulting in the formation of an alkoxydi-methylsulfonium chloride (32). 

A spontaneous cyclization occurs by effect of the Hiinig s base, added during the decomposition of the activated alcohols. This is a rare case in which a ketone condenses in situ with a stabilized phosphonate anion after a Swern oxidation. The condensation is facilitated by the formation of a six-membered ring, and by the relatively high reactivity of a ketone, possessing two activating oxygens at the a-position. 

Nonetheless, very often activated allylic alcohols are persistent enough at low temperature, so as to allow a normal Swern oxidation with an added base.235... 

The surplus activated DMSO, which remains unreacted after the activation of the alcohol during a Swern oxidation, decomposes on heating, generating the highly reactive species H2C=S(+)-Me (page 97). This species can react with tertiary alcohols present in the molecule, resulting in the formation of a methylthiomethyl ether.237... 

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. 

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. 

This is a rare case in which a 1,5-diol is transformed into a lactone by a Swern oxidation. The oxidation of the primary alcohol into an aldehyde is followed by the formation of a lactol by attack of the tertiary alcohol. At this point, in spite of the presence of Et3N, enough activated DMSO is present for the activation of the hydroxy group in the lactol and... 

Although the Corey-Kim oxidation is not used as often as the Swern oxidation—probably because of the bad odour of dimethyl sulfide—it offers the advantage of allowing an operation above -25°C. Typically, NCS (A-chlorosuccinimide) and Me2S are mixed in toluene at 0°C, resulting in the formation of a precipitate of activated DMSO. The reaction mixture is cooled to ca. —25°C and the alcohol is added for activation. This is followed by addition of Et3N and allowing the reaction to reach room temperature. 

The activation of DMSO by electrophilic reagents such as oxallyl chloride or trifluoroacetic anhydride (TFAA) (among many others) produces an oxidant capable of oxidizing primary alcohols to aldehydes in high yields. This oxidation is called the Swern oxidation and yields the aldehyde (oxidized product) by reductive elimination of dimethylsulfide (reduced product) and proceeds under mild, slightly basic conditions. It is a second widely used and effective oxidative method for the production of aldehydes from primary alcohols. 

The oxidation of primary or secondary alcohols to aldehydes or ketones respectively with dimethyl sulphoxide activated by oxalyl chloride has wide applicability (Swern oxidation).243b The initial reaction between the acid chloride and dimethyl sulphoxide in dichloromethane solvent is vigorous and exothermic at — 60 °C and results in the formation of the complex (7) this complex spontaneously decomposes, even at this low temperature, releasing carbon dioxide and carbon monoxide to form the complex (8). The alcohol is added within 5 minutes, followed after 15 minutes by triethylamine. After a further 5 minutes at low temperature the reaction mixture is allowed to warm to room temperature and work-up follows standard procedures. The ratio of reactants is dimethyl sulphoxide oxalyl chloride alcohol triethylamine 2.2 1.1 1.0 5. 

Fig. 17.13. Mechanism of the Swern oxidation of alcohols. The actual reagent is an "activated DMSO" (compound B or D), which reacts with an alcohol with formation of A or C, respectively. Dissociation leads to the sulfonium salt E, which is then converted into the sulfonium ylide F after NEt3 addition and raising the temperature from -60 to -45 °C. /3-Elimination via a cyclic transition state generates the carbonyl compound and dimethyl sulfide from F.

Ube Industries LtdinYamaguchi, Japan, and Kyoto University investigated the Swern oxidation for pharmaceutical intermediates [57,58]. In this reaction, alcohols are oxidized to carbonyl compounds using dimethyl sulfoxide. The reaction variant using dimethyl sulfoxide activated by trifluoroacetic anhydride (shown below) has found industrial application, but is limited to low-temperature operation (—50 °C or below) to avoid decomposition of an intermediate. 

Nucleophilic Attack at Halogen. This field of activity continues to be dominated by applications of well-known phosphine-positive halogen combinations. Alcohols can be oxidised to the related aldehydes and ketones under mild conditions by the DMSO-Ph3PX2 system, which provides an alternative to the Swern oxidation." The triphenylphosphine-iodine system has been... 

A commonly used, protected carbohydrate containing a secondary hydroxy group is diiso-propylideneglucofuranose 23. Oxidation to the corresponding ketone 24 illustrates some of the most widely applied methods for oxidation of secondary alcohols (O Table 4). Again, the reactions can be divided into three main categories oxidations mediated by activated DMSO, oxidations with chromium(VI) oxides, and oxidations catalyzed by mthenium oxides. For oxidations with activated DMSO the Swern procedure is the most widely used [27]. 

Those who ve learned use the Swern (John L. Wood). The Swern oxidation is a very reliable oxidation, and is likely the oxidation of choice when the temperature can be carefully controlled (see Tidwell, T. T. Org. React. 1990, 39, 297-572). However, the active chlorosulfonium intermediate decomposes above approximately -60 °C. Therefore, alternative dehydrating agents have been used (for useful reviews see Mancuso, A. J. Swern, D. Synthesis 1981,165 Lee, T. V. Oxidation Adjacent to Oxygen of Alcohols by Activated DMSO Methods. In Comprehensive Organic Synthesis Trost, B. M., Ed. Pergamon Press Oxford, 1991 Vol. 3, 291-304). A representative list is shown below. 

C.i. Swern Oxidation. The variation that is probably the most common in synthesis was discovered by Swern, who found that DMSO can be activated for the oxidation of alcohols by addition of trifluoroacetic anhydride. 6 The reaction is usually done in dichloromethane at temperatures below -30°C. The initially... 

In a later study, Helquist and co-workers adapted this methodology for preparing an advanced optically active intermediate in a synthetic approach to type A streptogramin antibiotics. Treatment of 960 and activated zinc with 957 afforded the alcohol (not shown) that was subjected to a Swern oxidation to produce the desired ,/i-diene 961 (Scheme 1.257). The authors noted that the addition reaction yielded 50% of the intermediate alcohol together with 30—40% recovered 960 regardless of the amount of 957 used. 

DMP is especially useful for the oxidation of the optically active, epimerization-sensitive substrates without loss of enantiomeric purity [1224,1241,1242], In a typical example, DMP was found to be a superior oxidant for the efficient, epimerization-free synthesis of optically active N-protected a-amino aldehydes 879 from the corresponding N-protected 3-amino alcohols 878 (Scheme 3.353) [1224]. In contrast, the Swern oxidation of amino alcohols 878 afforded products 879 of only 50-68% ee. 

K. Omura, D. Swern, Oxidation of alcohols by activated dimethyl sulfoxide a preparative, steric and mechanistic study, Tetrahedron 1978, 34, 1651—1660. 

Primary alcohols are cleanly oxidized to aldehydes (not to carboxylic acids as with Jones reagent), secondary alcohols yield ketones, and tertiary alcohols are again unre-active. Therefore, a Swem oxidation accomplishes the same transformations as PCC. Hence, in Example 10.11, the same products would be obtained with a Swern oxidation as with the application of PCC. 

One of the most used alcohol oxidations in organic synthesis is the Swern oxidation. A large number of variants exist for this reaction, but a common one involves DMSO, oxalyl chloride, and a base (pyridine, dimethylaminopy-ridine, and triethylamine are common). The currently accepted mechanism is shown below along with electron pushing for some steps. The first part of the mechanism involves activation of DMSO by reaction with oxalyl chloride. This is followed by nucleophilic attack of the alcohol on this activated species, creating an alkoxysulfonium intermediate. 

In recent years, chromium reagents have become less popular. Although inexpensive and effective, they are rather toxic and some are carcinogenic. Disposal of waste products also presents an issue. Many researchers now use the Swern oxidation—this uses dimethylsulfoxide as the oxidant, and the alcohol is activated with oxalyl chloride. The mechanism is shown in Figure 19.19. The advantages of the process are the lack of Cr(VI), anhydrous conditions and... 

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