Swem oxidation primary alcohols

The Swem Oxidation of alcohols avoids the use of toxic metals such as chromium, and can be carried out under very mild conditions. This reaction allows the preparation of aldehydes and ketones from primary and secondary alcohols, resp. Aldehydes do not react further to give carboxylic acids. A drawback is the production of the malodorous side product dimethyl sulphide. 

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. 

Like the Swem oxidation, the Dess-Martin periodinane (DMP) reagent oxidizes primary alcohols to aldehydes and secondary alcohols to ketones without using chromium or other heavy-metal compounds. The reaction with DMP takes place under mild conditions (room temperature, neutral pH) and gives excellent yields. The DMP reagent, which owes its oxidizing ability to a high-valence iodine atom, is a commercially available solid that is easily stored. 

Primary alcohols are oxidized to carboxylic acids by chromium-containing reagents and to aldehydes by PCC or a Swem oxidation. Secondary alcohols are oxidized to ketones. Tollens reagent can oxidize only aldehydes. A peroxyacid oxidizes an aldehyde to a carboxylic acid, a ketone to an ester (in a Baeyer-Villiger oxidation), and an alkene to an epoxide. Alkenes are oxidized to 1,2-diols by potassium permanganate (KMn04) in a cold basic solution or by osmium tetroxide (OSO4). 

Swem oxidation A mild oxidation, using DMSO and oxalyl chloride, that can oxidize primary alcohols to aldehydes and secondary alcohols to ketones, (p. 465) tosylate ester An ester of an alcohol with para-toluenesulfonic acid. Like halide ions, the tosylate anion is an excellent leaving group, (p. 469)... 

The Swem oxidation oxidizes primary alcohols to aldehydes and secondary alcohols to ketones using dimethyl sulfoxide and oxalyl chloride, followed by reaction with triethylamine. The actual oxidizing agent is the dimethylchlorosulfonium ion, (CH3)2SC1. (To see how this compound is formed from the reactants, see Problem 77 in Chapter 17.) Propose a mechanism for the oxidation. (Hint the first step is an Sn2 reaction, the last step is an E2 reaction.)... 

The aldehyde function at C-85 in 25 is unmasked by oxidative hydrolysis of the thioacetal group (I2, NaHCOs) (98 % yield), and the resulting aldehyde 26 is coupled to Z-iodoolefin 10 by a NiCh/CrCH-mediated process to afford a ca. 3 2 mixture of diaste-reoisomeric allylic alcohols 27, epimeric at C-85 (90 % yield). The low stereoselectivity of this coupling reaction is, of course, inconsequential, since the next operation involves oxidation [pyridinium dichromate (PDC)] to the corresponding enone and. olefination with methylene triphenylphosphorane to furnish the desired diene system (70-75% overall yield from dithioacetal 9). Deprotection of the C-77 primary hydroxyl group by mild acid hydrolysis (PPTS, MeOH-ClHhCh), followed by Swem oxidation, then leads to the C77-C115 aldehyde 28 in excellent overall yield. 

With ring G in place, the construction of key intermediate 105 requires only a few functional group manipulations. To this end, benzylation of the free secondary hydroxyl group in 136, followed sequentially by hydroboration/oxidation and benzylation reactions, affords compound 137 in 75% overall yield. Acid-induced solvolysis of the benzylidene acetal in 137 in methanol furnishes a diol (138) the hydroxy groups of which can be easily differentiated. Although the action of 2.5 equivalents of tert-butyldimethylsilyl chloride on compound 138 produces a bis(silyl ether), it was found that the primary TBS ether can be cleaved selectively on treatment with a catalytic amount of CSA in MeOH at 0 °C. Finally, oxidation of the resulting primary alcohol using the Swem procedure furnishes key intermediate 105 (81 % yield from 138). 

The Homer-Emmons addition of dialkyl alkoxycarbonylmethylenephosphonates to aldehydes has been widely used to generate a,3-unsaturated esters which, in turn, can be reduced to allylic alcohols. Under the original conditions of the Homer-Emmons reaction, the stereochemistry of the a, 3-unsatu-rated ester is predominantly trans, and therefore the tranr-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,3-unsaturated ester to predominantly cis. Diisobutylaluminum hydride (DIBAL) has frequently bem used for the reduction of the alkoxycarbonyl group to the primary alcohol functionality. The aldehyde needed for reaction with the Homer-Emmons reagent may be derived via Swem oxidation of a primary alcohol. The net result is that one frequently sees the reaction sequence shown in equation (1) used for the preparation of (3 )- and (3Z)-allylic alcohols. 

Aldol reaction of (5)-2-benzyloxypropanal with the lithium enolate of methyl 2-methoxy-propanoate gives a 7 2 1 mixture of (3-hydroxyesters (Scheme 13.70). After protection of the alcohol moiety, the isomeric mixture is reduced with LiAlH4 and the resulting primary alcohols separated by chromatography on silica gel. Oxidation of the major alcohol 223 (isolated in 40% yield) into an aldehyde is followed by Wittig methylenation. This provides 224. Hydroboration of 224 gives a primary alcohol that is oxidized (Swem) into aldehyde 225. Hydrogenation yields L-cladinose, a saccharide moiety of erythromycin A [127]. 

In some cases a two-step protocol is a milder procedure for oxidation of a primary alcohol to a carboxylic acid. The first step is then usually a Swem oxidation of the alcohol to the... 

Phosphonylation of a -3-(9-isopropylidene-a -pyridoxyl chloride via a Michaelis-Becker reaction, followed by deprotection with 1 M HCl and oxidation of the resulting primary alcohol with MnOj, produces diethyl (4-fonnyl-3-hydroxy-2-methyl-5-pyridyl)methylphosphonate (Scheme 5.38), an analogue of pyridoxal 5 -phosphate whose 5-position side chain has been replaced by a phospho-nomethyl group. The alcohol oxidation step can be accomplished with a wide range of reagents, such as activated MnOj in CHCI3 at room temperature (53%), PCC in CH2CI2 (83-86%), or the Swem reaction (>95%). ... 

Recently, a new class of odorless and nonvolatile organosulfur compounds grafted to imidazolium ionic liquid scaffold has been synthesized and used effectively for the oxidation of primary allylic and benzylic alcohols into aldehydes and secondary alcohols to ketones under Swem oxidation conditions [65],... 

The preparation of disaccharide 11.39 is outlined in Scheme 13. Condensation of 11.42 with 11.43 using TMSOTf as a promoter afforded disaccharide 11.47 in 81% yield. Treatment with aqueous TFA followed by acetylation replaced the isopropylidene moiety with two acetate groups, and subsequent de-levulinoylation with hydrazine acetate gave the primary alcohol 11.48. A Swem oxidation of the primary... 

Initially, Swem et al. reported the oxidation of sterically hindered alcohols to carbonyls with a dimethyl sulfoxide-trifluoroacetic anhydride complex.7 These reactants included primary alcohols such as 2,2-dimethyl-l-phenyl-propanol 3 and secondary alcohols, for example, 2-adamantanol 4. 

A few years later the Swem laboratory then developed an activator which they claimed to be the most successful in activating dimethyl sulfoxide toward oxidation, namely, oxalyl chloride. Since oxalyl chloride reacted violently and exothermically with dimethyl sulfoxide, successful activation required the use of low temperatures to form the initial intermediate.6 Swem et al. reported the oxidation of long chain primary alcohols to aldehydes which was previously unsuccessful by first converting to the sulfonate ester (either mesylate or tosylate) and then employing the dimethyl sulfoxide-acetic anhydride procedure. They found that long-chain saturated, unsaturated, acetylenic and steroidal alcohols could all be oxidised with dimethyl sulfoxide-oxalyl chloride in high yields under mild conditions. 

The versatility and efficiency of the Swem conditions means that they can also be applied to various functional groups to effect different transformations other than just oxidations of alcohols. For example, primary amides have been converted to nitriles using the Swem reagents as dehydrating agents.42 Although different activators of DMSO were tested, for example, the S03-pyridine complex and TFAA, oxalyl chloride was found to be the best based on the yield of the final product. 

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