Swern oxidation primary alcohols

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. 

Whereas the original Moffat-Pfitzner oxidation employs dicyclohexylcarbodiimide to convert DMSO into the reactive intermediate DMSO species 1297, which oxidizes primary or secondary alcohols via 1298 and 1299 to the carbonyl compounds and dicyclohexylurea [78-80], subsequent versions of the Moffat-Pfitzner oxidation used other reagents such as S03/pyridine [80a, 83] or oxalyl chloride [81-83] to avoid the formation of dicyclohexylurea, which is often difficult to remove. The so-called Swern oxidation, a version of the Moffat-Pfitzner oxidation employing DMSO/oxalyl chloride at -60°C in CH2CI2 and generating Me2SCl2 1277 with formation of CO/CO2, has become a standard reaction in preparative organic chemistry (Scheme 8.31). 

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). 

Since the primary alcohol groups of dehydroiridodiol can be converted to the corresponding aldehydes, a pathway to dehydroiridodial (56) could be opened by Swern oxidation in excellent yield as well (Scheme 1.2.13). 

The Homer-Emmons addition of dialkyl carboalkoxymethylenephosphonates to aldehydes [22] has been widely used to generate a,p-unsaturated esters which, in turn, can be reduced to allylic alcohols. Under the original conditions of the Homer-Emmons reaction, the stereochemistry of the oc,(3-unsaturated ester is predominantly trans and therefore the trans allylic alcohol is obtained upon reduction. Still and Gennari have introduced an important modification of the Homer-Emmons reaction, which shifts the stereochemistry of the a,[i-unsaturated ester to predominantly cis [23], Diisobutylaluminum hydride (DIBAL) has frequently been used for reduction of the alkoxycarbonyl to the primary alcohol functionality. The aldehyde needed for reaction with the Homer-Emmons reagent may be derived via Swern oxidation [24] of a primary alcohol. The net result is that one frequently sees the reaction sequence shown in Eq. 6A. 1 used for the net preparation of 3E and 3Z allylic alcohols. 

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. 

Primary TMS and TES ethers205 are deprotected and transformed into the corresponding aldehydes under Swern conditions. Other less labile silyl ethers—such as TBS ethers as well as secondary TMS and TES ethers—, remain unaffected. This allows to perform selective oxidations of primary alcohols in the presence of secondary ones by persilylation of poliols by TMS or TES, followed by selective oxidation of the primary silyl ethers to aldehydes under Swern conditions. 

Primary amides react under Swern conditions, producing the corresponding nitriles213 and minor amounts of iminosulfurans.210 Nonetheless, there is some report depicting the selective oxidation of alcohols in the presence of primary amides.214 Secondary and tertiary amides remain unaffected. 

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. 

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... 

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. 

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. 

Odourless and non-volatile organosulfur compounds grafted to an imidazolium ionic liquid scaffold has been synthesized. The sulfoxides have been used for an efficient oxidation of primary allylic and benzylic alcohols into aldehydes and secondary alcohols to ketones under Swern oxidation conditions and the corresponding sulfides can be recovered and recycled.110... 

Discussion The primary alcohol is oxidized in the standard Swern procedure to... 

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. 

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. 

TMS ethers of primary alcohols and most secondary alcohols do not survive even the simplest synthetic manipulations — especially if protic solvents are involved. For example, Swern oxidation or Collins oxidation conditions will cleave a primary TMS ether and perform the oxidation in the presence of a secondary TMS ether.3 Owing to the sensitivity of TMS ethers., deprotection can usually be achieved under very mild conditions (e,g., acetic acid or potassium carbonate in methanol). The rate of hydrolysis depends on both steric and electronic effects with hindered environments decreasing the rate and electron-withdrawing substituents on the hydroxyl function increasing the rate. In a synthesis of Zaragozic Acid A. the... 

First, the double bond in commercially available i -citronellol (20) is hydrogenated by stirring with palladium on charcoal under a hydrogen atmosphere. Then, the primary alcohol functionality in 35 is oxidized to the aldehyde via a Swern oxidation. 

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. 

The following Swern oxidation is an inexpensive, mild and fast transformation. It provides aldehydes starting from primary alcohols in the absence of water, exclusively. Other mild oxidation methods for the formation of aldehydes are known Dess-Martin periodinane (DMP), o-iodoxybenzoic acid (IBX), chromium(III) reagents, tetramethylpiperidine 7V-oxide and sodium hypochlorite (TEMPO/NaOCl), tetrapropylammonium perruthenate and N-methylmorpholine 7V-oxide (TPAP/NMO), " and palladium(II)-catalyzed oxidations are reported. ... 

In the first step of this reaction sequence, the primary alcohol 21 is oxidized to the corresponding aldehyde 38 in a Parikh-Doering oxidation which is related to the Swern oxidation. In general, this type of oxidation is conveniently carried out by addition of a solution of pyridine-SOs complex in DMSO to a mixture of the alcohol, DMSO and NEts. It can be assumed that dimethyl sulfoxide and sulfur trioxide react to form 0-dimethylsulfoxonium sulfate 40, which then further reacts with primary alcohol 39 to give 0-alkyl dimethylsulf-oxonium intermediate 41. Then, sulfonium salt 42 is formed and subsequently deprotonated by NEts to give sulfonium ylide 43. Finally, an intramolecular p-elimination occurs to provide the desired aldehyde 44 and dimethyl sulfide. 

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