Swern oxidation reaction temperature

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. 

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. 

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 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. 

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. 

The Swern oxidation uses dimethyl sulfoxide (DMSO) as the oxidizing agent to convert alcohols to ketones and aldehydes. DMSO and oxalyl chloride are added to the alcohol at low temperature, followed by a hindered base such as triethylamine. The reactive species (CH3)2SC1, formed in the solution, is thought to act as the oxidant in the Swem oxidation. Secondary alcohols are oxidized to ketones, and primary alcohols are oxidized only as far as the aldehyde. The by-products of this reaction are all volatile and are easily separated from the organic products. 

In the Swern oxidation, the reaction of oxalyl chloride with DMSO may generate chlorodimethylsulfonium chloride (A), which reacts with the alcohol to give alkoxysulfonium ion intermediate B. The base, typically triethylamine, deprotonates the alkoxysulfonium ion B to give the sulfur ylide C, which decomposes to give DMS and the desired aldehyde or ketone (Scheme 7.7). The temperature of this reaction is kept near —60 to -78°C. 

One example is Swern oxidation, which uses oxalyl chloride and DMSO and is particularly suitable for the selective oxidation of alcohols to aldehydes or ketones. The disadvantages of this oxidation method are the need for low temperatures, the smell of the dimethyl sulfide formed and the possible oxidation of other heteroatoms. Dess-Martin periodinane (DMP, 5) or iodoxybenzoic acid (IBX, 6) are also common oxidizing agents. The main advantage of these two methods is the short reaction time at room temperature. However, typical problems are the low solubility of IBX and the formation of byproducts. In this context, Finney et al. have reported an interesting procedure avoiding these problems by a variation of the temperature IBX is sufficiently soluble in solvents such as ethyl acetate or dichloromethane at elevated temperatures, whereas it is insoluble in these solvents at room temperature. Because of this, the remaining IBX as well as the IBX-derived byproducts can be separated from the reaction mixture by simple filtration. These reisolated IBX byproducts can then be reoxidized and reused. 

Adding reagents at low temperatures can create problems if the freezing point of the reagent is above the temperature of the reaction. For instance, oxalyl chloride (mp —10 to — 8°C) is often used for Swern oxidations of secondary alcohols. Typically this reaction is conducted at —78 to — 70°C, and oxalyl chloride is added to the surface of the reaction. Under these conditions oxalyl chloride may freeze at the point it exits the addition line. Diluting with solvents allows compounds with relatively high freezing points to be added to cold reactions. 

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... 

Swem showed that the permanganate oxidation of oleic acid (245) was pH dependent. Earlier, Lapworth and Mottram oxidized oleic acid to 9,10-dihydroxy stearic acid, 246,344 jp essentially quantitative yield by what might be considered standard conditions for hydroxylation 0.1% oleic acid, no more than 1% KMnOq, short reaction time (5 min), slight excess of alkali and a reaction temperature of 0-10°C.344 Swern found that... 

Intramolecular cycloaddition reactions with 2-azadienes have found limited apphcation in organic synthesis, however an efficient route to the daphniphyllum alkaloids makes use of such a cycloaddition. " The 2-azadiene 101 was formed in situ from the diol 100 by Swern oxidation (to the dialdehyde) and addition of ammonia (3.82). Cycloaddition in the presence of acetic acid at room temperature gave the complex ring system 102. If the reaction mixture is warmed to 70 °C... 

Thus, hydrogenolysis of 63 affords the pyranose tautomer 64. Wittig reaction of 64 using propyltriphenylphosphonium bromide and potassiiun tert-butoxide in dry THF at room temperature for 30 min and then at 80 °C for 20 min affords an /Z mixture of the alkenes 65 in 58% yield. Hydrogenation of 65 followed by Swern oxidation of the reduced product affords the lactol 67 which has been previously transformed in three steps to canadensohde (68) (Scheme 14) [40]. 

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... 

Experimental Protocol. The experimental protocol for using fluorous sulfoxide 1 in the Swern oxidation is similar to the original one where DMSO is used except for the work-up details. The reactions are typically run in anhydrous CH2CI2 at —30°C for 1-2 h and then warmed to room temperature for 1 h. The reaction mixture is diluted with H2O, washed with saturated NH4CI solution, and then extracted with CH2 CI2. CH2 CI2 is subsequently... 

One such replacement is the Swern oxidation. The oxidizing agent itself is a chlorosulfonium salt, which is generated at -78 C by the reaction of DMSO with oxalyl chloride. (Running this reaction at ambient temperature is explosive ) Slow addition of the alcohol at low temperature, followed by the addition of a tertiary amine such as triethyl amine (EtjN), yields the product. 

A general method for the preparation of a-alkoxyacroleins, which indudes a Swern oxidation step, has been reported [1348]. Swern oxidation of 1806 with oxalyl chloride/Me2SO at —78 °C, followed by treatment with triethylamine, gave the corresponding aldehydes 1807. As the crude reaction mixtures were allowed to warm to ambient temperature (0.5-3 h), j8-elimination gave alkoxy aldehydes 1808 in 70-93% yield. 

The use of trifluoroacetic anhydride for the activation of DMSO in the oxidation of alcohols was first attempted by Albright and Goldman in 196 5.119,120 According to these authors, who tried the reaction at room temperature, trifluoroacetic anhydride is not effective in the activation of DMSO. Later, Swern et al. made a detailed study of the interaction of DMSO with TFAA,121 and proved that the resulting activated DMSO is stable at low temperature and can be used in the oxidation of alcohols. In... 

Few oxidation methods have enjoyed the almost immediate success of the Swern procedure for the oxidation of alcohols. Since the publication of three foundational papers161 in 1978-79, Swern has become the de facto oxidation method by default whenever activated DMSO is desired. It offers the advantage of quite consistent good yields in many substrates, with an operation performed under very low temperature and mild conditions. Swern s procedure consists of the oxidation of an alcohol using DMSO, activated by reaction with oxalyl chloride. According to Swern, oxalyl chloride is the most effective activator of DMSO examined by his group.162 It must be mentioned that Swern s research team is probably the one that has tried the highest number of DMSO activators for the oxidation of alcohols. 

According to the standard protocol (procedure A) as described by Swern et at., the alcohol is allowed to react with activated DMSO for 15 min at low temperature (normally —78 to —50°C). This is followed by the addition of triethylamine, which reacts with the activated alcohol, while the reaction is left to reach room temperature. This standard protocol, involving the generation of activated DMSO in CH2C12 at low temperature (ca. -60°C), followed by activation of the alcohol for 15 min, addition of triethylamine and after 5 min allowing the reaction to heat up slowly to room temperature, is found suitable for most substrates. However, some variations have been introduced to suit the oxidation of diverse alcohols. 

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. 

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