Swern protocol

There are many methods for selectively oxidizing an alcohol to the corresponding aldehyde. Of course you have to think about the stability of your molecule when you decide which procedure to choose, but ecological and economic aspects are also very important. Chromium-free oxidations such as Swern conditions or Dess-Martin periodinane (DMP) are preferred over the classic methods that employ Jones reagent, Collins reagent or PCC/PDC. For the mechanism of the here used Swern protocol, see Chapter 5, p. 86. 

The primary alcohol Z-13 is oxidized to aldehyde 14 (Segment BC) using the Swern protocol. Typically, Swern oxidation is performed in CH2CI2 using oxalylchloride, dimethyl sulfoxide and triethylamine at -78 °C. In transformations of chiral, enolizable alcohols, milder bases such as A-methyl morpholine or sterically hindered bases such as diisopropylethylamine Hunig s base) are widely used. Swern oxidation is an inexpensive, fast (typically several minutes), mild and selective oxidation method for primary and secondary alcohols. For the detailed mechanism, see Chapter 5, p. 86. 

The primary alcohol at C-1 is oxidized to the corresponding aldehyde using the Swern protocol in the next step of this reaction scheme. For the detailed mechanism see Chapter 5, p. 86. 

There are several variations of the Swern protocol, where the oxalyl chloride is replaced by another activator. Acetic anhydride or trifluoroacetic anhydride is sometimes used. Carbodiimides (R-N=C=N-R) are yet another alternative—the reaction in that case is called a Pfltzner-Mojfatt oxidation. 

Alcohols react with compound 22 at low temperature in ca. 30 min, yielding an alkoxydimethylsulfonium salt 24 and one equivalent of trifluoroacetic acid. This mixture is normally stable at room temperature for several days. Nonetheless, alkoxydimethylsulfonium salts, derived from alcohols whose radicals are able to stabilize carbocations—particularly allylic and benzylic alcohols—suffer solvolyses by the action of trifluoroacetic acid from 0°C to room temperature, already in the absence of an amine, yielding the corresponding trifluoroacetates. This differential stability of alkoxydimethylsulfonium salts, derived from diverse alcohols, dictate different protocols in the Omura-Sharma Swern oxidation depending on the alcohol (vide infra). 

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. 

In the first step Crimmins and co-workers used the Swern oxidation protocol to provide a ketone as prochiral, sp2-center. 

The protected methyl glycoside 3 is converted to the corresponding aldehyde by Swern oxidation using oxalyl chloride activated DMSO. Further reaction with triethyl phosphonoacetate and sodium hydride -known as the Horner-Wadsworth-Emmons reaction - provides selectively the trans et /Tun saturated ester 4 in 72 % yield. This valuable alternative to the Wittig olefination protocol uses phosphonate esters as substrates which are readily available from alkyl halides and trialkyl phosphites via the Arbuzov rearrangement.9 co2Et Reaction of the phosphonate with a suitable base gives the... 

Crimmins s TiCL -mediated asymmetric aldol condensation protocol was used in the enantioselective total synthesis of (9S)-dihydroerythronolide A (68)25 (Scheme 2.lx). Swern oxidation of the primary alcohol 69 provided the aldehyde 70 in almost quantitative yield, which underwent asymmetric aldol condensation with the titanium enolate of (A )-4-bcnzyl-3-propionyloxa/,olidin-2-onc (26M) in the presence of (-)-sparteine to afford the aldol adduct desired (71) as a single diastereomer. 

Nishide, K., Ohsugi, S.-i., Fudesaka, M., Kodama, S., Node, M. New odorless protocols for the Swern and Corey-Kim oxidations. Tetrahedron Lett. 2002, 43, 5177-5179. 

Besides the one-step procedure described here, conversion of ester 1 to aldehyde 2 can be accomplished by reduction of the ester with lithium aluminum hydride, and subsequent oxidation of the alcohol produced using a Swern-oxidation protocol 8.14-16... 

The oxidation of alcohols to carbonyl compounds is one of the most fundamental and important processes in the fine chemical industry. The classical methodology is based on the stoichiometric use of heavy metals, notably Cr and Mn (1,2). Alternatively metal-free oxidation, such as the Swern and Pfitzner-Moffat protocols, is based on e.g., dimethylsulfoxide as oxidant in the presence of an activating reagent such as N,N -dicyclohexylcarbodiimide, an acid anhydride or acid halide (3). Although the latter methods avoid the use of heavy metals, they usually involve moisture-sensitive oxidants and environmentally undesirable reaction media, such as chlorinated solvents. The desired oxidation of alcohols only requires the formal transfer of two hydrogen atoms, and therefore the atom economy of these methods is extremely disadvantageous. The current state of the art in alcohol oxidations... 

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... 

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