Swem oxidant with oxalyl chloride

A new synthesis of reserpine (Scheme 19)60 makes use of a very neat synthesis of cw-hydroisoquinoline derivatives, e.g. (Ill), by means of a Diels- Alder /Cope rearrangement sequence. Manipulation of (111) by unexceptional methods then gives (112), which possesses the required stereochemistry in ring E. Oxidative cyclization of (112) affords 3-isoreserpinediol (113) but, unfortunately, some inside isomer, originating from the cyclization of C-2 with C-21, is also obtained. The synthesis also loses some elegance in the multi-stage conversion of 3-isoreserpinediol into 3-isoreserpine (114), since, in the Swem oxidation of the C-16 aldehyde cyanhydrin by means of DMSO with oxalyl chloride as activator, the over-oxidized products (115) and (116) were obtained. However, reduction of (115) gave 3-isoreserpine (114), which has previously been converted into reserpine by four different methods. 

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 conversion of 44 to the corresponding aldehydes was carried out by using a Swem oxidation. Thus, treatment of 44 with oxalyl chloride in dimethylsulfoxide at -60 °C followed by triethylamine, afforded aldehydes... 

Numerous procedures have been reported for the synthesis of iV-protected-a-amino aldehydes [78]. The A-protected a-amino aldehydes can be prepared either by oxidation of the corresponding A-protected j8-amino alcohols with oxidants such as pyridinium dichromate [79,80] or SOs-pyridine-di-methyl sulfoxide (DMSO) [81] or under Swem conditions [DMSO-oxalyl chloride-A,A-diisopropylethylamine (DIEA)] [81-83], by reduction of esters with diisobutyl aluminum hydride (DIBAL) [84], by reduction of A,A-disubstituted amides [85-87], by reduction of urethane-protected A-carboxy-... 

There are several methods reported in the literature for transforming vicinal diols into ct-diketones while avoiding the risk of C-C bond cleavage.26 Examples include the standard Swem conditions (dimethyl sulfoxide and oxalyl chloride followed by triethylamine), or the use of DMSO activated by acetic anhydride, pyridine-sulfur trioxide complex, or dicyclohexylcarbodiimide (Mq/J-att oxidation). Diones are also obtained by treatment with benzalacetone as a hydride acceptor in the presence of catalytic amounts of tris(triphenylphosphine)ruthenium dichlonde [(PPh RuCFl.27 Recent developments include the use of w-iodoxyben/.oic acid28 or the oxoammonium salt of 4-acctamidoletramethylpipcridine-1-oxyl and y -toluencNulfonic acid.29... 

Sulfur trioxide is one of many reagents [e.g.. DCC Ac20, (COC1) TPAA with which DMSO can be activated as an oxidizing reagent lor alcohols. Oxalyl chloride has found the widest application in the reaction named after Swem.Xi Structure 43 represents the activated species in the above oxidation. 

The maiin domain of oxidation with dimethyl sulfoxide is the conver-sionofprimary alcoholsinto aldehydes andofsecondaryalcoholsintoketones. These reactions are accomplished under very mild conditions, sometimes at temperatures well below 0 °C. The reactions require the presence of acid catalysts such as acetic anhydride [713, 1008, 1009], trifluoroacetic acid [1010], trifluoroacetic anhydride [1011, 1012, 1013], trifluorometh-anesulfonic acid [1014], phosphoric acid [1015, 1016], phosphorus pentox-ide [1006, 1017], hydrobromic acid [1001], sulfur trioxide [1018], chlorine [1019, 1020], A -bromosuccinimide [997], carbonyl chloride (phosgene) [1021], and oxalyl chloride (the Swem oxidation) [1022, 1023, 1024], Dimethyl sulfoxide also converts sufficiently reactive halogen derivatives. into aldehydes or ketones [998, 999] and epoxides to a-hydroxy ketones at -78 °C [1014]. 

The mechanism of the Swem oxidation has been studied in depth and the formation of an initial adduct 7 from the reaction between dimethyl sulfoxide and oxalyl chloride which then collapses to give a dimethylchlorosulfonium species 8 is clearly indicated by mechanistic studies.3,8 Reaction of 8 with an alcohol then produces the alkyoxysulfonium ion 9 which upon treatment with an amine base gives the ylide 10. Subsequent proton extraction gives the carbonyl product 2 with the release of dimethyl sulfide. 

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.)... 

Oxidation of primary and secondary alcohols to aldehydes and ketones with DMSO, oxalyl chloride, and a base is knovm as Swem-oxidation. When using oxalyl chloride as the dehydration agent, the reaction must be kept colder than —60°C to avoid side reactions, such as Pummerer rearrangement. In contrast, when trifluoroacetic anhydride is used instead of oxalyl chloride, the reaction can be warmed to —30 °C without side reactions. Microflow systems offer a smart approach for controlling the reaction... 

Another commoidy used oxidizing agent is DMSO together with a dehydrating agent such as acetic anhydride or oxalyl chloride (Swem oxidation) [41] as shown in Equation 6.24 [42]. 

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