Swern oxidations

Oxidation of alcohols to the corresponding carbonyl compounds using (COCl)2, DMSO, and quenching with EtsN. 

Nishide, K. Ohsugi, S.-i. Fudesaka, M. Kodama, S. Node, M. Tetrahedron Lett. 2002, 43, 5177. (New odorless protocols). 

Firouzabadi, H. Hassani, H. Hazarkhani, H. Phosphorus, Sulfur Silicon Related Elements 2003,178, 149. 

Oxidation of alkyl fluorosilanes to the corresponding alcohols. Cf. Fleming oxidation. 

The Petasis reagent (Me2TiCp2, dimethyltitanocene) undergoes similar olefi-nation reactions with ketones and aldehydes. The originally proposed mechanism [3] was very different from that of Tebbe olefmation. However, later experimental data seem to suggest that both Petasis and Tebbe olefmation share the same mechanism, i.e. the carbene mechanism involving a four-membered titanium oxide ring intermediate [6]. 

The first total synthesis of the marine dolabellane diterpene (+)-deoxyneodolabelline was achieved in the laboratory of D.R. WilliamsJ In the final step of the synthetic sequence, the oxidation of a secondary alcohol functionality of a 1,2-diol to the corresponding a-hydroxy ketone was required. Such 1,2-diols are known to be unstable under most oxidation conditions, and often glycol cleavage is observed. Indeed, when Dess-Martin and Ley oxidations were tried, the substrate suffered carbon-carbon bond cleavage. However, under the Swern oxidation conditions, the desired a-hydroxy ketone was isolated in a 65% yield. Interestingly, the substrate was a mixture of four inseparable diastereomeric diols (obtained in a McMurry reaction), which gave two easily separable ketone products, one of which was the natural product. 

Martin and co-workers utilized a double Swern oxidation in their synthesis of ircinal A and related manzamine alkaloids. The advanced tricyclic did intermediate was first subjected to the Swern oxidation conditions at -78 °C to afford the corresponding dialdehyde in excellent yield. In the next step, the dialdehyde was exposed to excess Wittig reagent under salt-free conditions to form the two terminal alkenes. 

The convergent total synthesis of the mytotoxic (+)-asteltoxin was accomplished by J.K. Cha et al. The coupling of the two main fragments was achieved by the HWE olefinatlon of a jb/s(tetrahydrofuran) aldehyde with an a-pyrone phosphonate. The b/s(tetrahydrofuran) aldehyde was prepared by the Swern oxidation of the corresponding b/s(tetrahydrofuran) primary alcohol. Interestingly, under the oxidation conditions there was no epimerization of the a-stereocenter, but during the HWE olefinatlon a small amount of C8 epimer was formed. 

Many types of functional groups are tolerated in a Suzuki reaction, and the yields are often good to very good. The presence of a base, e.g. sodium hydroxide or sodium/potassium carbonate, is essential for this reaction. The base is likely to be involved in more than one step of the catalytic cycle, at least in the transmetal-lation step. Proper choice of the base is important in order to obtain good results. In contrast to the Heck reaction and the Stille reaction, the Suzuki reaction does not work under neutral conditions. 

The S ern 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. 

In order to enable the dimethyl sulfoxide 3 to oxidize the alcohol substrate effectively, it has to be converted into an reactive agent. This is carried out by treatment with oxalyl chloride 4, hence leading to sulfonium ions 5 or 6 as the active species  

The ionic species 5, as well as 6, represent the so-called activated dimethyl sulfoxide. Variants using reagents other than oxalyl chloride for the activation of DMSO are known. In the reaction with an alcohol 1, species 5, as well as 6, leads to the formation of a sulfonium salt 7  

Upon addition of a base—triethylamine is often used—the sulfonium salt 7 is deprotonated to give a sulfonium ylide 8. The latter decomposes into the carbonyl compound 2 and dimethyl sulfide 9 through /3-elimination via a cyclic transition state. 

---

The 6-endo activated epoxy alcohol cyclization process was also expected to play a central role in the annulation of pyran ring G of the natural product (see Scheme 22). Silylation of the free secondary hydroxyl group in compound 131 furnishes, after hydrobora-tion/oxidation of the double bond, compound 132. Swern oxidation of alcohol 132 produces an aldehyde which reacts efficiently with (ethoxycarbonylethylidene)triphenylphosphorane in the presence of a catalytic amount of benzoic acid in benzene at 50 °C, furnishing... 

Swern oxidation of N-unsubstituted aziridine-2-carboxylate 210 (Scheme 3.77) resulted in the formation of 2H-azirine 211 in >90% yield [95] Similar oxidation of 212 (Scheme 3.78) afforded azirine 213 in 60% yield [66]. 

Swern oxidation of N-unsubstituted aziridine-2-phosphonates resulted in the formation of both 2H-azirine-2-phosphonates and 2H-azirine-3-phosphonates [81, 83]. Treatment of ds-aziridine-2-phosphonate 226 (Scheme 3.84) with DM SO/ (COCl)2/Et3N afforded azirine-phosphonates 227 and 228, with the former predominating [81]. Under similar conditions, however, trans-aziridine-2-phospho-... 

Silyl enol ethers, 23, 77, 99-117,128 Silyl enolates, 77 Silyl peroxides, 57 Silyl triflate, 94 Silyl vinyl lithium, 11 (E)-l -Silylalk-1 -enes, 8 Silylalumimum, 8 Silylation, 94 reductive, 26 a-C-Silylation, 113 O-Silylation.99,100 / -SilyIketone, 54 non-cydic, 55 Silylmagnesium, 8 Silyloxydienes, 112 Sodium hexamethyldisilazide, 89 Sodium thiosulphate pentahydrate, 59 Stannylation, see Hydrostannylation Stannylethene, 11 (Z)-Stilbene, 70 (E)-Stilbene oxide, 70 /3-Styryltrimethylsilane, 141 Swern oxidation. 84,88... 

A highly remarkable and entirely unexpected conversion of aziridine esters 21 into azirine esters 22 was accomplished by subjecting the aziridine to a Swern oxidation (Scheme 11). 

The regiochemistry of this elimination reaction resembles that observed by Davis et al. (see Scheme 9) [23]. The special nature of the bonds in three-mem-bered rings is probably responsible for this exclusive regiochemistry. It is of interest to note that 3,3-dimethylaziridine-2-carboxylic ester indeed leads to the corresponding 3H-azirine ester upon Swern oxidation here there is, of course, no choice. 

The Swern oxidation was also employed by Davis and McCoull [251 for the synthesis of 2iT-azirinephosphonates 27 and 28 from the corresponding aziridines 26 (Scheme 14). Interestingly, in this case a mixture of the regioiso-meric azirines is obtained, whereby the proton abstraction adjacent to the phos-... 

A range of 6-substituted 2-amino-e-caprolactams 66 has been synthesized by a sequence published by Robl et al. for investigating the generation of peptidomimetics. After Swern oxidation of the dipeptide 63, the corresponding... 

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). 

Preparatively useful procedures based on acetic anhydride,25 trifluoroacetic anhydride,26 and oxalyl chloride27 have been developed. The last method, known as the Swern oxidation, is currently the most popular. 

A number of modifications were made to meet scale-up requirements. In the preparation of the common intermediate, LiBH4 was used in place of LiAlH4 in Step A-2 and a TEMPO-NaOCl oxidation was used in place of Swern oxidation in Step A-3. Some reactions presented difficulty in the scale-up. For example, the boron enolate aldolization in Step B-l gave about 50% yield on the 20- to 25-kg scale as opposed to greater than 75% on a 50-g scale. The amide formation in Step B-3 was modified to eliminate the use of trimethylaluminum, and the common intermediate 17 could be prepared on a 30-kg scale using this modified sequence. The synthesis of the C(l)-C(6) segment V was done by Steps C-l to C-5 in 66% yield on the scale of several kg. 

The drug candidate 1 was prepared from chiral cyclopentanol 10 as shown in Scheme 7.3. Reaction of 10 with racemic imidate 17, prepared from the corresponding racemic benzylic alcohol, in the presence of catalytic TfOH furnished a 1 1 mixture of diastereomers 18 and 19 which were only separated from one another by careful and tedious chromatography. Reduction of ester 18 with LiBH4 and subsequent Swern oxidation gave aldehyde 20 in 68% yield. Reductive animation of 20 with (R)-ethyl nipecotate L-tartrate salt 21 and NaBH(OAc)3 and subsequent saponification of the ester moiety yielded drug candidate 1. 

The second synthesis of crystalline 43 was reported by Mori as summarized in Scheme 62 [93]. The building block (4.R,5S)-A was prepared by an enzymatic process, while another building block C was synthesized via Sharpless asymmetric epoxidation. Coupling of A with C gave D, which was cyclized under Op-polzer s conditions to give crystalline E. When E was oxidized with Dess-Martin periodinane or tetra(n-propyl)ammonium perruthenate or Jones chromic acid, crystalline 43 was obtained. Swern oxidation or oxidation with 2,2,6,6-tetramethylpiperidin-1 -oxyl of E afforded only oily materials. Accordingly, oxidation of E to 43 must be executed extremely carefully. A synthesis of oily 43 was reported by Gil [94]. 

---