Swern oxidation sensitivity

Functional Group and Protecting Group Sensitivity to Omura-Sharma-Swern Oxidation... 

As expected, acid sensitive functionalities, including THP,135 Tr,136 TBS137 and t-Bu138 ethers, orthoesters,139 acetals140 and glycosides,137a 141 as well as Boc-protected142 amines, are resistant to Omura-Sharma-Swern oxidations. 

The decomposition of acid-sensitive substrates during Swern oxidations can also be explained by the presence of adventitious hydrogen chloride. This can be avoided by the use of freshly distilled oxalyl chloride and carefully dried DMSO.174... 

These reactions only operate on very sensitive substrates, and protecting groups removable under basic conditions normally resist a Swern oxidation. 

The Swern oxidation shows a great regioselectivity for the oxidation of alcohols, in the presence of other functionalities with a high sensitivity for oxidants. For example, sulfides, thioacetals, disulfides (see page 146) and even selenides200 resist the action of Swern oxidation. 

A Swern oxidation is followed by an in situ aldol condensation, thanks to the use of excess of base. During this very elegant stereoselective construction of a highly functionalized cyclohexene, the hindered base diisopropylethylamine must be used in order to keep the sensitive stereochemistry around the ketone moiety. 

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. 

During Swern oxidations, adventitious HC1 may be present either due to the use of impure oxalyl chloride, or due to the hydrolysis of some chlorine-containing chemical, caused by employing wet DMSO. Adventitious HC1 may cause acid-induced side reactions on sensitive substrates.174,246... 

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... 

WIN55,212-2 (49) has been synthesized as shown in Scheme 13 (65). Swern oxidation of 50 afforded the very sensitive a-amino ketone 51. Reductive cyclization of 51 with Raney-Ni provided the key intermediate 52. The enantiomers of 52 were obtained by crystallization with (+)- and (-)-dibenzoyltar-taric acid (DBT). Hydrazine 54 obtained from enantiomerically pure 53 was then converted to enamino ketone 55, which when refluxed in the presence of acetic acid yielded (R)-(-i-)-WIN55,212-2 (49) in 44% yield. 

In numerous synthetic studies it has been demonstrated that DMP can be used for a selective oxidation of alcohols containing sensitive functional groups, such as unsaturated alcohols [297,1215-1218], carbohydrates and polyhydroxy derivatives [1216, 1219-1221], silyl ethers [1222,1223], amines and amides [1224-1227], various nucleoside derivatives [1228-1231], selenides [1232], tellurides [1233], phosphine oxides [1234], homoallylic and homopropargylic alcohols [1235], fluoroalcohols [1236-1239] and boronate esters [1240]. Several representative examples of these oxidations are shown below in Schemes 3.349-3.354. Specifically, the functionalized allylic alcohols 870, the Baylis-Hillman adducts of aryl aldehydes and alkyl acrylates, are efficiently oxidized with DMP to the corresponding a-methylene-p-keto esters 871 (Scheme 3.349) [1217]. The attempted Swern oxidation of the same adducts 870 resulted in substitution of the allylic hydroxyl group by chloride. 

DMP is especially useful for the oxidation of the optically active, epimerization-sensitive substrates without loss of enantiomeric purity [1224,1241,1242], In a typical example, DMP was found to be a superior oxidant for the efficient, epimerization-free synthesis of optically active N-protected a-amino aldehydes 879 from the corresponding N-protected 3-amino alcohols 878 (Scheme 3.353) [1224]. In contrast, the Swern oxidation of amino alcohols 878 afforded products 879 of only 50-68% ee. 

A notable feature associated with some of these methods is that high yields of a,6-unsaturated esters are obtained even with rather sensitive aldehydes substituted by unprotected hydroxy-, nitro-, or keto-groups. Exceptionally sensitive aldehydes which may even defy isolation can be generated and trapped in situ by carrying out a Swern oxidation of the corresponding alcohol at -78 C and then adding a stabilized phosphorane [e.g. (176)] (Scheme 15). Remarkably high yields can be obtained in the... 

The oxidation of alcohols with (l,l-dimethylethyl)benzene-sulfenamide is extremely mild and many sensitive functional groups such as epoxides and alkenes are tolerated hy the reaction conditions (eq 5). In the case of alcohol 1, oxidation with tetrapropylammonium perruthenate (TPAP) resulted in only 58% yield and Swern oxidation was unsuccessful. Epimerizable aldehydes such as the protected phenylglycinol 2 do not undergo racemization when oxidized (eq 6). ... 

This alcohol containing a very sensitive diazirine moiety can be efficiently oxidized with DMP, while other oxidants like Swern, MnC>2, PCC, PDC and CAN were not successful. 

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... 

Functional Group Compatibility. The neutral conditions of these oxidations have been utilized to provide improved yields with acid sensitive substrates compared to the well established Swern method (eqs 9-10). ... 

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